The effect of GnRH-a on the angiogenesis of endometriosis.

PURPOSE: Neoangiogenesis is necessary for adhesion and invasiveness of endometriotic lesions in women affected by endometriosis. Vascular endothelial growth factor (VEGF) is one of the main components of angiogenesis and is part of the major pathway tissue factor (TF)-protease activated receptor-2 (PAR-2)-VEGF that leads to neoangiogenesis. Specificity protein 1 (SP1) is a transcriptional factor that has recently been studied for its crucial role in angiogenesis via a specific pathway. We hypothesize that by blocking angiogenetic pathways we can suppress endometriotic lesions. Gonadotrophin-releasing hormone-agonists (GnRH-a) are routinely used, especially preoperatively, in endometriosis. It would be of great interest to clarify which angiogenetic pathways are affected and, thereby, pave the way for further research into antiangiogenetic effects on endometriosis. METHODS: We used quantitative real-time polymerase chain reaction (qRT-PCR) to study mRNA expression levels of TF, PAR-2, VEGF, and SP1 in endometriotic tissues of women who underwent surgery for endometriosis and received GnRH-a (leuprolide acetate) preoperatively. RESULTS: VEGF, TF, and PAR-2 expression is significantly lower in patients who received treatment (p < 0,001) compared to those who did not, whereas SP1 expression is not altered (p = 0.779). CONCLUSIONS: GnRH-a administration does affect some pathways of angiogenesis in endometriotic lesions, but not all of them. Therefore, supplementary treatments that affect the SP1 pathway of angiogenesis should be developed to enhance the antiangiogenetic effect of GnRH-a in patients with endometriosis. TRIAL REGISTRATION: Clinicaltrial.gov ID: NCT06106932.

Placental mRNA Expression of Neurokinin B Is Increased in PCOS Pregnancies with Female Offspring.

Current research suggests that polycystic ovary syndrome (PCOS) might originate in utero and implicates the placenta in its pathogenesis. Kisspeptin (KISS1) and neurokinin B (NKB) are produced by the placenta in high amounts, and they have been implicated in several pregnancy complications associated with placental dysfunction. However, their placental expression has not been studied in PCOS. We isolated mRNA after delivery from the placentae of 31 PCOS and 37 control women with term, uncomplicated, singleton pregnancies. The expression of KISS1, NKB, and neurokinin receptors 1, 2, and 3 was analyzed with real-time polymerase chain reaction, using ß-actin as the reference gene. Maternal serum and umbilical cord levels of total testosterone, sex hormone-binding globulin (SHBG), free androgen index (FAI), androstenedione, dehydroepiandrosterone sulfate (DHEAS), Anti-Mullerian hormone (AMH), and estradiol were also assessed. NKB placental mRNA expression was higher in PCOS women versus controls in pregnancies with female offspring. NKB expression depended on fetal gender, being higher in pregnancies with male fetuses, regardless of PCOS. NKB was positively correlated with umbilical cord FAI and AMH, and KISS1 was positively correlated with cord testosterone and FAI; there was also a strong positive correlation between NKB and KISS1 expression. Women with PCOS had higher serum AMH and FAI and lower SHBG than controls. Our findings indicate that NKB might be involved in the PCOS-related placental dysfunction and warrant further investigation. Studies assessing the placental expression of NKB should take fetal gender into consideration.

Poseidon and Caeneus: a case of pubertal gender inversion in Greek mythology.

Disorders of sex development (DSDs) are very frequently encountered in ancient Greek mythology. One of the most striking types of DSD described in many myths is gender transformation wherein a female becomes a male or vice versa. Herein, we present via the marvelous myth of Poseidon and Caeneus a case of pubertal gender inversion. A medical interpretation of the myth whereby we attempt to form a diagnosis of this case of DSD is also presented.

Sexual function scores are associated with arterial stiffness in postmenopausal women.

BACKGROUND: Female sexual dysfunction (FSD) has been suggested to be correlated with the burden of cardiovascular risk factors. AIM: We aimed to evaluate the possible association between functional indices of vascular function and FSD scores in apparently healthy postmenopausal women. METHODS: This cross-sectional study included 116 postmenopausal women who underwent assessment of endothelial function with measurement of flow-mediated dilation (FMD) of the branchial artery and arterial stiffness estimation with measurement of the carotid-femoral pulse wave velocity (PWV). We used the Greene Climacteric Scale to evaluate vasomotor symptomatology, the Female Sexual Function Index (FSFI) to evaluate FSD and the Beck Depression Inventory to evaluate mood disorder. Low sexual function was defined as an FSFI score <26.55. OUTCOMES: These included FSFI and low sexual function scores as well as measures of PWV and FMD. RESULTS: Sexual function scores were associated with measures of blood pressure (normal vs low sexual function; systolic blood pressure: 120.2 ± 15.0 mm Hg vs 113.4 ± 14.6 mm Hg; analysis of covariance P = .026; diastolic blood pressure: 75.9 ± 10.5 mm Hg vs 70.3 ± 9.9 mm Hg; analysis of covariance P = .012; both adjusted for age, body mass index, current smoking, and PWV). Systolic blood pressure, but not diastolic blood pressure, was associated with FSFI (B = 0.249, P = .041) and PWV (B = 0.392, P < .001). PWV measures were associated with FSFI (B = -0.291, P = .047) and pulse pressure (B = 0.355, P = .017). FMD measures were also associated with FSFI (B = 0.427, P = .033). All models were adjusted for age, body mass index, current smoking, insulin resistance, vasomotor symptomatology, and Beck Depression Inventory. CLINICAL IMPLICATIONS: Our findings demonstrate that lower scores of sexual function are associated with deteriorated vascular function mainly manifested as arterial stiffening, further contributing to systolic blood pressure changes. STRENGTHS AND LIMITATIONS: The strength of this study is the carefully selected healthy sample of postmenopausal women, with simultaneous assessment of climacteric symptomatology and mood disorders. The limitations include the small sample size, the cross-sectional design, and the recruitment of consecutive outpatients of a university menopause clinic. CONCLUSION: Longitudinal studies and interventions to improve FSD should further assess the clinical relevance of these findings.

Anti-Müllerian hormone: a novel biomarker for aggressive prostate cancer? Emerging evidence from a prospective study of radical prostatectomies.

PURPOSE: Prostate cancer patients are a heterogeneous group as regards the aggressiveness of the disease. The relationship of steroid hormones with the aggressiveness of prostate cancer is unclear. It is known that the anti-Müllerian hormone (AMH) inhibits prostate cancer cell lines in vitro. The aim of this study is to investigate the relationship of AMH and steroid hormones with the aggressiveness of prostate cancer. METHODS: This was a prospective study of consecutive radical prostatectomy patients. We measured the following hormones: total testosterone, sex hormone-binding globulin, albumin, luteinizing hormone, follicle-stimulating hormone, estradiol, dehydroepiandrosterone sulfate, androstenedione, and AMH. The minimum follow-up after radical prostatectomy was 5 years. For the aggressiveness of prostate cancer, we considered the following three variables: post-operative Gleason score (GS) ≥ 8, TNM pΤ3 disease, and prostate-specific antigen (PSA) biochemical recurrence (BCR). RESULTS: In total, 91 patients were enrolled. The mean age and PSA were 64.8 years and 9.3 ng/dl, respectively. The median post-operative GS was 7. Low AMH blood levels were correlated with higher post-operative GS (p = 0.001), as well as with PSA BCR (p = 0.043). With pT3 disease, only albumin was (negatively) correlated (p = 0.008). ROC analysis showed that AMH is a good predictor of BCR (AUC 0.646, 95% CI 0.510-0.782, p = 0.043); a cutoff value of 3.06 ng/dl had a positive prognostic value of 71.4% and a negative prognostic value of 63.3% for BCR. Cox regression analysis showed that AMH is a statistically significant and independent prognostic marker for BCR (p = 0.013). More precisely, for every 1 ng/ml of AMH rise, the probability for PSA BCR decreases by 20.8% (HR = 0.792). Moreover, in Kaplan-Meier analysis, disease-free survival is more probable in patients with AMΗ ≥ 3.06 ng/ml (p = 0.004). CONCLUSIONS: Low AMH blood levels were correlated with aggressive prostate cancer in this radical prostatectomy cohort of patients. Therefore, AMH could be a prognostic biomarker for the aggressiveness of the disease.

Diabetes Remission After LRYGBP With and Without Fundus Resection: a Randomized Clinical Trial.

BACKGROUND: Glycemic control, after metabolic surgery, is achieved in two stages, initially with neuroendocrine alterations and in the long-term with sustainable weight loss. The resection of the gastric fundus, as the major site of ghrelin production, is probably related with optimized glucose regulation. The aim of the present study is to investigate whether the modification of laparoscopic Roux-en-Y gastric bypass (LRYGBP) with fundus resection offers superior glycemic control, compared to typical LRYGBP. MATERIALS AND METHODS: Participants were 24 patients with body mass index (BMI) ≥40kg/m2 and type II diabetes mellitus (T2DM), who were randomly assigned to undergo LRYGBP and LRYGBP with fundus resection (LRYGBP+FR). Gastrointestinal (GI) hormones [ghrelin, glucagon-like-peptide-1 (GLP-1), peptide-YY (PYY)] and glycemic parameters (glucose, insulin, HbA1c, C-peptide, insulinogenic index, HOMA-IR) were measured preoperatively, at 6 and 12 months during an oral glucose tolerance test (OGTT). RESULTS: Ninety-five percent of patients showed complete remission of T2DM after 12 months. LRYGBP+FR was not related with improved glycemic control, compared to LRYGBP. Ghrelin levels were not significantly reduced at 6 and 12 months after LRYGBP+FR. GLP-1 and PYY levels were remarkably increased postprandially in both groups at 6 and 12 months postoperatively (p<0.01). Patients who underwent LRYGBP+FR achieved a significantly lower BMI at 12 months in comparison to LRYGBP (p<0.05). CONCLUSION: Fundus resection is not associated with improved glycemic regulation, compared to typical LRYGBP and the significant decrease in BMI after LRYGBP+FR has to be further confirmed with longer follow-up.

Climacteric symptoms, age, and sense of coherence are associated with sexual function scores in women after menopause.

BACKGROUND: Postmenopausal sexual function presupposes the integration of hormonal, neural, and vascular interactions and is subject to optimal crosstalk among psychological, interpersonal, cultural, and environmental factors. Sense of coherence (SOC) reflects a person's ability to cope with stressors and may influence the occurrence of menopausal symptoms and sexual dysfunction. AIM: To investigate the association of severity of climacteric symptoms, cardiometabolic risk factors, and SOC with sexual function in postmenopausal women. METHODS: Overall 281 sexually active postmenopausal women without significant psychopathology or cardiovascular disease attending the Menopause Unit of Aretaieion Hospital were evaluated by the Female Sexual Function Index (FSFI), Greene Climacteric Scale, Beck Depression Scale, and Sense of Coherence Scale. Hormonal and biochemical parameters and cardiometabolic risk factors were evaluated. FSFI scores <26.5 were considered pathologic. OUTCOMES: Total and subdomain scores of sexual response were determined. RESULTS: Pathologic FSFI scores were found in 79.7% of the sample. Linear models of multivariable regression analysis showed that FSFI scores were associated with (1) Beck scores (b = -0.200; 95% CI, -0.472 to -0.073, P = .001), vasomotor symptom severity (b = -0.324; 95% CI, -0.985 to 0.051; P < .001), and age and (2) SOC (b = 0.150, 95% CI, 0.036-0.331; P = .008), vasomotor symptom severity (b = -0.361; 95% CI, -0.743 to 0.245; P < .001), and age. Both models were adjusted for menopausal age, diabetes mellitus, hypertension, type of menopause, and menopausal hormone therapy intake. SOC was associated with Beck depression scores (ß = -0.487, P < .001; Greene Climacteric Scale total scores, ß = -0.199, P < .001). FSFI score <26.5 vs >26.5 was associated with SOC (odds ratio, 0.982; 95% CI, 0.563 to 1.947; P = .006) and moderate to severe vasomotor symptom severity (odds ratio, 2.476; 95% CI, 1.478 to 3.120; P = .009) independent of age, diabetes mellitus, hypertension, menopausal hormone therapy intake, type of menopause, or Beck depression classification. CLINICAL IMPLICATIONS: The results indicate the importance of psychometric assessment of postmenopausal women when presenting with scores of low sexual function. The severity of vasomotor symptoms should also be addressed in any case. STRENGTHS AND LIMITATIONS: This is the first study investigating the relationship between SOC and sexuality in menopause in a carefully selected homogenous population. Limitations included the cross-sectional design and the fact that sexual distress was not assessed. CONCLUSIONS: Pathologic FSFI scores were highly prevalent in this sample of postmenopausal women. FSFI is associated positively with age and severity of vasomotor symptoms and negatively with SOC.

Heterozygous mutations in SOX2 may cause idiopathic hypogonadotropic hypogonadism via dominant-negative mechanisms.

Pathogenic SRY-box transcription factor 2 (SOX2) variants typically cause severe ocular defects within a SOX2 disorder spectrum that includes hypogonadotropic hypogonadism. We examined exome-sequencing data from a large, well-phenotyped cohort of patients with idiopathic hypogonadotropic hypogonadism (IHH) for pathogenic SOX2 variants to investigate the underlying pathogenic SOX2 spectrum and its associated phenotypes. We identified 8 IHH individuals harboring heterozygous pathogenic SOX2 variants with variable ocular phenotypes. These variant proteins were tested in vitro to determine whether a causal relationship between IHH and SOX2 exists. We found that Sox2 was highly expressed in the hypothalamus of adult mice and colocalized with kisspeptin 1 (KISS1) expression in the anteroventral periventricular nucleus of adult female mice. In vitro, shRNA suppression of mouse SOX2 protein in Kiss-expressing cell lines increased the levels of human kisspeptin luciferase (hKiss-luc) transcription, while SOX2 overexpression repressed hKiss-luc transcription. Further, 4 of the identified SOX2 variants prevented this SOX2-mediated repression of hKiss-luc. Together, these data suggest that pathogenic SOX2 variants contribute to both anosmic and normosmic forms of IHH, attesting to hypothalamic defects in the SOX2 disorder spectrum. Our study describes potentially novel mechanisms contributing to SOX2-related disease and highlights the necessity of SOX2 screening in IHH genetic evaluation irrespective of associated ocular defects.

The role of the gastric fundus in glycemic control.

PURPOSE: Ghrelin, one of the most studied gut hormones, is mainly produced by the gastric fundus. Abundant evidence exists from preclinical and clinical studies underlining its contribution to glucose regulation. In the following narrative review, the role of the gastric fundus in glucose regulation is summarized and we investigate whether its resection enhances glycemic control. METHODS: An electronic search was conducted in the PubMed® database and in Google Scholar® using a combination of medical subject headings (MeSH). We examined types of metabolic surgery, including, in particular, gastric fundus resection, either as part of laparoscopic sleeve gastrectomy (LSG) or modified laparoscopic gastric bypass with fundus resection (LRYGBP + FR), and the contribution of ghrelin reduction to glucose regulation. RESULTS: Fourteen human studies were judged to be eligible and included in this narrative review. Reduction of ghrelin levels after fundus resection might be related to early glycemic improvement before significant weight loss is achieved. Long-term data regarding the role of ghrelin reduction in glucose homeostasis are sparse. CONCLUSION: The exact role of ghrelin in achieving glycemic control is still ambiguous. Data from human studies reveal a potential contribution of ghrelin reduction to early glycemic improvement, although further well-designed studies are needed.

Ghrelin, glucagon-like peptide-1, and peptide YY secretion in patients with and without weight regain during long-term follow-up after bariatric surgery: a cross-sectional study.

Introduction: Weight loss after bariatric surgery is attributed, at least in part, to the altered gastrointestinal (GI) hormone secretion, which is thought to be responsible for a number of beneficial metabolic effects. Material and methods: We conducted a cross-sectional study. Twelve patients who underwent laparoscopic sleeve gastrectomy (SG) and 20 patients who underwent a variant of biliopancreatic diversion with Roux-en-Y gastric bypass and long limbs (BPD/RYGB-LL) were evaluated ≥ 7 years postoperatively. Ghrelin, glucagon-like peptide-1 (GLP-1), and peptide YY (PYY) secretion were compared between patients with successful weight loss maintenance (WM group) and patients with weight regain (WR group). Results: In both types of surgery, standard liquid mixed meal (SLMM) ingestion did not result in significant changes in fasting GI hormone levels. Fasting ghrelin levels did not differ between the WM group and the WR group in both types of surgery. In SG patients, SLMM ingestion elicited greater suppression of ghrelin levels in the WM group (p = 0.032). No difference in GLP-1 secretion was observed between the 2 groups of patients in both types of surgery. When patients were examined, regardless of the type of bariatric surgery they had undergone, postprandial PYY levels were lower in the WM group (p < 0.05), while fasting and postprandial PYY levels were correlated positively with an increase in body mass index (BMI) in the evaluation (Spearman's rho ≥ 0.395, p < 0.03). Conclusions: Our data do not support the hypothesis that long-term weight regain after bariatric surgery is associated with an unfavourable GI hormone secretion pattern.

The p190 RhoGAPs, ARHGAP35, and ARHGAP5 are implicated in GnRH neuronal development: Evidence from patients with idiopathic hypogonadotropic hypogonadism, zebrafish, and in vitro GAP activity assay.

PURPOSE: The study aimed to identify novel genes for idiopathic hypogonadotropic hypogonadism (IHH). METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Endocrine disruptors in ancient times and Greek mythology: the spring of Salmacis and the curse of Hermaphroditus.

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.

ACTH vs steroids for the treatment of acute gout in hospitalized patients: a randomized, open label, comparative study.

The management of acute gout in the hospital setting may be challenging since most patients are elderly with multiple unstable comorbidities. However, there are no prospective clinical trials for hospitalized patients with gout to guide optimal management. Evidence indicates that steroids or adrenocorticotropic hormone (ACTH) may be effective and safe therapeutic options for these patients. This study aimed at directly comparing the efficacy and safety of ACTH vs betamethasone for the treatment of gout in hospitalized patients. This is the first prospective clinical trial for hospitalized patients with gout. We designed a randomized, open label study to assess the efficacy and safety of a single intramuscular injection of either ACTH or betamethasone in hospitalized patients with acute gout. Primary efficacy endpoints were the change in intensity of pain as recorded using a Visual Analogue Scale (VAS) at baseline compared to 24 h (ΔVAS24h), and 48 h. Moreover, we assessed safety and effects on the hypothalamic-pituitary-adrenal (HPA) axis, glucose and lipid homeostasis, bone metabolism, electrolytes and renal function. 38 patients were recruited. Both treatments were highly effective. The mean ± SE ΔVAS24h and ΔVAS48h for ACTH was 4.48 ± 0.29 and 5.58 ± 0.26, respectively. The mean ± SE ΔVAS24h and ΔVAS48h for betamethasone was 4.67 ± 0.32 and 5.67 ± 0.28, respectively. Direct comparison between the two groups at 24 h and 48 h did not show statistically significant differences. Both treatments were well tolerated and safe. The effects on all metabolic parameters were mostly minimal and transient for both treatments. However, ACTH may affect less the HPA axis and bone metabolism compared to betamethasone, thus leading to the conclusion that. ACTH and betamethasone are effective and safe for the management of acute gout in hospitalized patients but that ACTH may associate with less disturbance of the HPA axis and bone metabolism. Our data support the use of both drugs as first line treatments for hospitalized patients with gout.Clinical trial registration: ClinicalTrials.gov NCT04306653.

Expression stability of ACTB, 18S, and GAPDH in human placental tissues from subjects with PCOS and controls: GAPDH expression is increased in PCOS.

PURPOSE: The aim was to assess the expression stability of three commonly used reference genes, namely, ß-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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Differences in thyroid function tests after administration of a single supraphysiological dose of ACTH or a high dose of a synthetic steroid.

OBJECTIVE: 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). DESIGN: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Wnt4, Wnt6 and ß-catenin expression in human placental tissue - is there a link with first trimester miscarriage? Results from a pilot study.

BACKGROUND: Demystifying the events around early pregnancy is challenging. A wide network of mediators and signaling cascades orchestrate the processes of implantation and trophoblast proliferation. Dysregulation of these pathways could be implicated in early pregnancy loss. There is accumulating evidence around the role of Wnt pathway in implantation and early pregnancy. The purpose of this study was to explore alterations in the expression of Wnt4, Wnt6 and ß-catenin in placental tissue obtained from human first trimester euploid miscarriages versus normally developing early pregnancies. METHODS: The study group consisted of first trimester miscarriages (early embryonic demises and incomplete miscarriages) and the control group of social terminations of pregnancy (TOPs). The placental mRNA expression of Wnt4, Wnt6 and ß-catenin was studied using reverse transcription PCR and real time PCR. Only euploid conceptions were included in the analysis. RESULTS: Wnt4 expression was significantly increased in placental tissue from first trimester miscarriages versus controls (p = 0.003). No significant difference was documented in the expression of Wnt6 (p = 0.286) and ß-catenin (p = 0.793). There was a 5.1fold increase in Wnt4 expression for early embryonic demises versus TOPs and a 7.6fold increase for incomplete miscarriages versus TOPs - no significant difference between the two subgroups of miscarriage (p = 0.533). CONCLUSIONS: This is, to our knowledge, the first study demonstrating significant alteration of Wnt4 expression in human placental tissue, from failed early pregnancies compared to normal controls. Undoubtedly, a more profound study is needed to confirm these preliminary findings and explore Wnt mediators as potential targets for strategies to predict and prevent miscarriage.

Severe hypovitaminosis D in pregnant refugees arriving in Europe: neonatal outcomes and importance of prenatal intervention.

Adequate vitamin D levels are particularly important in pregnant women for both 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. VDD 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 (<10 ng/mL). As a result, most newborns had VDD, which affected refugee newborns to a greater extent. Our results suggest a need to screen newcomer children and pregnant women for VDD in all host countries around the world. Such a screen will appropriately guide early and effective interventions with the goal to prevent adverse neonatal and maternal outcomes.

Teenage pregnancies in Western Greece: experience from a university hospital setting.

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 < 0.001), and negative marital status (p < 0.001) in teenage mothers compared to pregnant women of AMA. There were no significant differences concerning other factors between the two groups. CONCLUSIONS: The findings of the present study raise concern regarding the perinatal, obstetric, and social consequences of teenage pregnancies in Greece. Extended studies that will include further information on antenatal care and detailed socioeconomic factors (i.e., level of education, income, and ethnicity) are required to formulate reliable conclusions concerning teenage pregnancies and their effect on maternal and neonatal health.

Shifting gears: Study of immune system parameters of male habitual marathon runners.

Aim: Marathon is a running event in which athletes must cover a distance of 42.195 km. In addition to participating in marathons, marathoners have incorporated extensive running into their lifestyle. In the present study, we investigated the effect of long-term strenuous exercise in the form of marathon running on the immune system. Methods & Results: We collected peripheral blood samples from 37 male marathoners before/after a race and 37 age/sex/body mass index (BMI)-matched healthy sedentary controls. Hematological and biochemical tests revealed race-induced leukocytosis attributable to neutrophilia and significant increases in plasma lactate dehydrogenase (LDH), creatine phosphokinase (CPK), and cortisol concentrations. Phenotypic analysis of lymphocytes revealed race-induced significant decrease in the number of lymphocytes, memory helper T (Th) cells, naive, memory and activated cytotoxic T (Tc) cells, natural killer (NK), NKT, and B1 cells, and a significant increase in the number of activated Th and regulatory Th cells (Tregs). Compared with controls, marathoners maintained significantly lower levels of memory and activated Th cells and higher levels of activated Tc and B1 cells. Measurement of plasma cytokine levels revealed a pro-inflammatory cytokine polarization that increased after the race. Examination of gene expression of cytokines and Th-cell signature transcription factors in peripheral blood mononuclear cells revealed a significant decrease in tumor necrosis factor α (TNF-α) and interleukin (IL)-17, and a significant increase in IL-6, IL-10 and forkhead box P3 (FoxP3) after the race. Compared with controls, marathoners maintained significantly higher levels of TNF-α. Assessment of the suppressive capacity of Tregs in co-cultures of isolated effector Th cells and Tregs showed significantly increased suppressive capacity of marathoners' Tregs after the race. Conclusions: Compared with controls, marathoners live with permanent changes in certain immune parameters. Marathoners exhibit a stable pro-inflammatory cytokine polarization that increases after the race and is counterbalanced by increased numbers of Tregs overexpressing FoxP3 and having increased suppressive capacity.

Impaired Sexual Function in Young Women With PCOS: The Detrimental Effect of Anovulation.

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 <.001, lubrication P value <.001, orgasm P value .001, satisfaction P value .001 and FSFI total score P value <.001). 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. Mantzou D, Stamou MI, Armeni AK, et al. Impaired Sexual Function in Young Women With PCOS: The Detrimental Effect of Anovulation. J Sex Med 2021;18:1872-1879.