Prevalence, distribution, and risk markers for the development of gonadal germ cell tumors in patients with certain types of disorders of sexual differentiation with Y chromosome - A retrospective study.

PURPOSE: To study the prevalence, subtypes, and risk markers for the development of gonadal germ cell tumors (GCT's) among disorders of sexual differentiation (DSD) patients with the Y chromosome. MATERIALS AND METHOD: Design: A retrospective review of the patient's case records from 2010 to 2020 in Government Medical College, Thiruvananthapuram, India was studied. The study participants included 54 subjects with DSD containing the Y chromosome. Demographic data, external masculinization scoring, associated congenital anomalies, karyotyping, intraoperative findings such as gonadal location and internal genital ducts, histopathology of the resected gonads, and its immunohistochemistry were collected. The prevalence of gonadal GCT's was estimated from paraffin-embedded gonadectomy samples (S = 82). RESULTS: The median age of occurrence of gonadal GCT's was 18 years. The prevalence of malignant gonadal GCT's was highest among the PAIS group (19.2%) followed by gonadal dysgenesis (15.8% each in MGD and CGD) and least among CAIS (7.7%) (p < 0.01). The most common type of malignant gonadal GCT's in the descending order of frequency was dysgerminoma, seminoma, mixed GCT, and yolk sac tumor. Multivariance logistic analysis showed post-puberty and the presence of congenital anomalies were associated with the occurrence of gonadal GCT's ( P < 0.01). CONCLUSION: The overall prevalence of gonadal GCT's (malignant and premalignant) among DSD with Y chromosomes is nearly 25%. Dysgerminoma is the most common malignant gonadal GCT's. Age at or above 18 years and the presence of congenital anomalies like renal agenesis, retroperitoneal vascular defects, and congenital diaphragmatic hernia were independent risk markers for the development of gonadal GCT's.

Clinical and Reproductive Characteristics of Patients with Mixed Gonadal Dysgenesis (45,X/46, XY).

INTRODUCTION: Mixed gonadal dysgenesis (MGD) or 45,X/46,XY mosaicism is a sex chromosomal disorder of sexual development. We aim to characterize the clinical and reproductive features of 45X/46 XY attending tertiary care center in Kerala. MATERIALS AND METHOD: Retrospective review of clinical records which include clinical presentation, hormonal profile, cytogenetics, psychosexual assessment, and histopathology of gonadectomy specimen of ten cases of 45X/46 XY mosaicism who attended Endocrinology/ OBG out patient department from 2008 to 2020. RESULTS: The mean ages of all the cases were 12 ± 3.79 years (± 2 SD). Short stature was universally seen. Virilisation was the most common manifestation (80%) followed by delayed puberty (20%). Autoimmune thyroid disease was seen in 40% of cases. We noticed a delayed presentation in our clinical study. 45X/46 XY subjects who wished to continue as female underwent gonadectomy and were feminized with hormone replacement therapy. Male 45X/46 XY who retained their undescended testis is planned for periodic surveillance for malignancy. CONCLUSION: 45X/46 XY may present like Turner's syndrome in clinical practice. Early counseling and gender assignment by a panel of specialists are crucial. Delayed presentation is less commonly encountered now a day and may pose a clinical challenge. Management in 45X/46 XY is multi-disciplinary which includes Turner's like surveillance, proper sex assignment, timely genital reconstruction surgeries, gonadectomy, gonadal monitoring, and hormonal replacement therapy is needed.

Sex Hormone-Binding Globulins and Testosterone Levels as a Risk Marker for Type 2 Diabetes Mellitus among Postmenopausal Women.

BACKGROUND: Endogenous sex hormones and sex hormone-binding globulins (SHBG) determine the risk of occurrence of Type 2 diabetes mellitus (T2DM) in postmenopausal (PM) women. AIMS: To investigate the association between sex hormones (estradiol and testosterone) and SHBG with plasma glucose, fasting insulin levels, HbA1c, and homeostasis model assessment insulin resistance (HOMA-IR) and also to investigate independent role of sex hormones in the occurrence of T2DM among PM. SETTINGS AND DESIGN: Cross-sectional case-control study. SUBJECTS AND METHODS: The present study was conducted in Endocrinology department Guwahati, Medical College, Assam, India. The participants included cases - PM women with T2DM (n = 100) and controls - Healthy PM women (n = 86). The medical history, clinical examination, and investigations including total testosterone, serum estradiol, SHBG, free testosterone index, high sensitivity C-reactive protein (hs-CRP), lipid profile, fasting insulin, fasting plasma glucose (FPG), and postprandial plasma glucose (PPPG) were done and analyzed. HOMA-IR was calculated. STATISTICAL ANALYSIS: Pearson correlation between sex hormone level and SHBG with plasma glucose, HbA1c, fasting insulin, hs-CRP, and HOMA-IR was seen. Multivariance logistic analysis was done to find the independent association between sex hormones/SHBG and the occurrence of T2 DM. P < 0.05 was considered statistically significant. RESULTS: Among the cases, a significant positive correlation was found between total testosterone/free testosterone index with waist circumference, FPG PPPG, HbA1c, fasting insulin, and HOMA-IR, and a significant negative correlation was found between SHBG and FPG, PPPG, HbA1c, fasting insulin, and HOMA-IR (P < 0.01). The logistic analysis showed total testosterone levels and SHBG are independently associated with the occurrence of T2 DM among PM (P < 0.01). CONCLUSION: SHBG and testosterone levels in PM can be a risk marker for the development of T2DM.

Hemoptysis: A Rare Presentation of Mixed Gonadal Dysgenesis.

The objective of the study was to present a case report on a phenotypic male mixed gonadal dysgenesis (MGD) who presented with hemoptysis due to secondary lung metastasis from dysgerminoma. Phenotypic male MGD (45, X/46, XY) with primary infertility and hemoptysis participated in the study. This study was conducted at a tertiary care center. Laparoscopic visualization of gonads and presence of Müllerian/ Wolffian structures were ascertained. Gonadectomy of intra abdominal dysgenetic gonad were done. Fluorescence in situ hybridization analysis was done in gonadal tissue to find the presence of Y chromosome. Intra-abdominal gonad showed dysgerminoma changes. Müllerian structures in the form of rudimentary uterus and fallopian tubes were seen. Left inguinal gonad showed normal testicular structures. Chemotherapy for secondary lung metastasis contemplated.

"Spectrum of 46 XY Disorders of Sex Development": A Hospital-based Cross-sectional Study.

BACKGROUND: Disorders of sex development (DSD) are a wide range of relatively rare conditions having diverse pathophysiology. Identification of an underlying cause can help in treating any coexisting hormone deficiencies and can help with anticipating any other immediate or long-term health concerns. OBJECTIVE: To study the clinical and biochemical profile of patients with 46 XY DSD along with androgen receptor (AR) gene mutation status in selected group of patients. METHODS: A cross-sectional study was conducted after enrolling the eligible DSD patients. Thorough elicitation of history and detailed clinical examination was done. Assays for luteinizing hormone, follicle-stimulating hormone, testosterone, dihydrotestosterone, androstenedione, AMH & Inhibin B (where indicated), and human chorionic gonadotropin stimulation were done as per protocol. RESULTS: In total, 48 patients were included in the study. Ambiguous genitalia (58.3%) followed by hypospadias (33.3%) were common presentation. Androgen biosynthetic defect were the most commonly encountered diagnosis followed by androgen insensitivity syndrome (AIS). Swyer syndrome was diagnosed in 4.2% of cases; partial gonadal dysgenesis, ovotesticular DSD, and vanishing testis syndrome contributed to 2% of cases each. Eight cases (16.7%) who presented with isolated proximal and midshaft hypospadias for whom no diagnosis was found were categorized in the "etiology unclear" group. AR gene mutation analysis designed against specific exons did not yield any results. CONCLUSION: 46 XY DSD is a heterogeneous group of patients with a varying age of presentation and a diverse clinical profile. Most patients are reared as males and maintained the same gender identity except in isolated cases. Diagnosis of AIS remains a clinical challenge as a definite hormonal criterion does not exist and genetic mutations in AR gene may be negative. Flanking region sequencing, whole genome sequencing, and promoter region sequencing may reveal pathogenic variants. Variations in other genes regulating AR pathway may also be candidates to be studied.

Long-acting porcine ACTH stimulated salivary cortisol in the diagnosis of adrenal insufficiency.

BACKGROUND: Synacthen stimulated salivary cortisol has been previously evaluated and found beneficial in the diagnosis of adrenal insufficiency (AI), especially in situations with altered cortisol-binding protein (CBG) levels. Unfortunately, Synacthen is not marketed in many parts of the world whereas porcine sequence corticotrophin (Acton Prolongatum) is readily available. This study aimed to find the diagnostic accuracy of Acton prolongatum stimulated salivary cortisol test (APSST) compared to the short synacthen test (SST). METHODS: Consecutive outpatients with suspected AI underwent SST initially, followed by APSST after 3 days. For APSST, saliva was collected at 0, 60 and 120 minutes after administering 30 units Acton Prolongatum intramuscularly. Serum and salivary cortisol were estimated using electrochemiluminescence assay. (Cobas e 411, Elecsys Cortisol II kits) RESULTS: Sixty-seven patients with clinically suspected AI were enrolled for the study. Based on SST, 35 patients were classified as having AI [primary AI (n=19) and secondary AI (n=16)] whereas 32 had normal glucocorticoid reserve. The area under receiver operator curve of 0.99 and 0.98 was observed for salivary cortisol values at 60 and 120 minutes, respectively, for APSST. A cut-off value of 18.5 nmol/L (0.67 µg/dL) and 29.3 nmol/L (1.06 µg/dL) at 60 and 120 minutes, respectively, had a sensitivity as well as specificity of 93%-100% in diagnosing AI. CONCLUSION: Salivary cortisol estimation following stimulation using intramuscular porcine ACTH (Adrenocorticotrophic hormone) (30 units) is an economical and accurate alternative to SST in the diagnosis of AI, m and its level of 30 nmol/L or more at 2 hours confirms adrenal sufficiency.

Efficacy and Safety of Once-Weekly Thyroxine for Thyroxine-Resistant Hypothyroidism.

CONTEXT: Noncompliance with thyroxine therapy is the most common cause of poor control of hypothyroidism. An open-label prospective study to compare once-weekly thyroxine (OWT) with standard daily thyroxine (SDT) was undertaken. DESIGN: Patients taking thyroxine doses of >3 µg/kg/d, with or without normalization of TSH, were included and administered directly observed OWT or nonobserved SDT according to patient preference based on their weight for 6 weeks. Furthermore, patients on OWT were advised to continue the same at home without supervision. RESULTS: Twenty six of 34 patients on OWT and 7 of 18 patients on SDT achieved a TSH <10 µIU/mL (P < 0.05), and 2 patients from the SDT arm were lost to follow-up. During home treatment, 15 of 25 at 12 weeks and 19 of 23 contactable patients at a median follow-up of 25 months maintained TSH below target. Thyroxine absorption test was unable to predict normalization of TSH at 6 weeks of OWT therapy. No adverse events were seen with OWT-treated patients over the 12-week follow-up period. OWT has significantly higher efficacy (OR = 5.1) than SDT for patients with thyroxine-resistant hypothyroidism and is not associated with side effects. CONCLUSION: OWT benefits a majority of patients in the long-term treatment of thyroxine-resistant hypothyroidism, in the real-world setting.

Long acting porcine sequence ACTH in the diagnosis of adrenal insufficiency.

OBJECTIVES: Injectable tetracosactide hexa-acetate, ACTH 1-24 (Synacthen), is not marketed in many countries including India, whereas Injectable long acting porcine sequence, ACTH 1-39 (Acton Prolongatum®) is easily available and much cheaper. This study aimed to find the diagnostic accuracy of ACTH stimulation test using i.m. Acton Prolongatum® (acton prolongatum stimulation test, APST) in comparison with Synacthen (short synacthen test, SST) for the diagnosis of glucocorticoid insufficiency. METHODS: Subjects with a suspicion of adrenal insufficiency based on clinical features underwent a SST with 250 µg Synacthen followed by APST using 30 units of Acton Prolongatum®. Serum cortisol levels were measured at 60 and 120 min following injection of Acton Prolongatum®. Stimulated peak cortisol of less than 18 µg/dL on SST was considered as adrenal insufficiency. RESULTS: Forty seven patients with mean age of 36.7 ± 14.4 years were enrolled for the study. Based on SST, twenty (n = 20) persons were classified as having adrenal insufficiency, whereas twenty-seven (n = 27) were found to be normal. Area under the curve of APST (at 120 min) was 0.986 when compared to SST, thus proving its high accuracy. A serum cortisol cut off value of 19.5 µg/dL at 120-min following stimulation with Acton Prolongatum® showed a sensitivity of 100% and specificity of 88%. CONCLUSION: ACTH stimulation test using Acton Prolongatum® is an economical and accurate alternative to the short Synacthen test.

Sex Hormone Levels - Estradiol, Testosterone, and Sex Hormone Binding Globulin as a Risk Marker for Atherosclerotic Coronary Artery Disease in Post-menopausal Women.

CONTEXT: Sex hormones levels determine the risk of occurrence of coronary artery disease (CAD) in post-menopausal (PM) women. AIMS: To investigate the relationship between sex hormones (estradiol and testosterone)/sex hormone binding globulin (SHBG) and cardiovascular risk factors in PM women. In addition, we learned the association between these sex hormones/SHBG and the occurrence of atherosclerotic CAD event in PM women. SETTINGS AND DESIGN: Cross-sectional case- control study. SUBJECTS AND METHODS: Subjects recruited in the present study were from the cardiology outpatient clinic or Emergency department Guwahati Medical College and Hospital, Assam. The subjects were grouped into two categories after appropriate exclusion criteria: Cases - PM women with documented CAD (n = 40) and controls - Healthy PM women (n = 30). The medical history, clinical examination, and investigations including serum estradiol, total testosterone, SHBG, free testosterone index (FTI), high-sensitivity C-reactive protein (hs-CRP), lipid profile, carotid intima-media thickness (CIMT), fasting plasma glucose (FPG), and postprandial plasma glucose (PPPG) were done and analyzed. STATISTICAL ANALYSIS USED: Pearson correlation between sex hormones and CAD risk factors was done. The association between sex hormones and CAD risk factors among PM women was analyzed by multiple logistic regression. The statistical significance was set at the 0.05 level. RESULTS: The mean age of all the subjects was 62.27 ± 6.9 years. Among the cases, a significant positive correlation was found between total testosterone/FTI and waist circumference, W/H ratio, triglyceride levels, hs-CRP, and CIMT (P < 0.01). In addition, a significant negative correlation was found between total testosterone and FTI with high-density lipoprotein-cholesterol levels (P < 0.01). The multiple logistic regression analysis showed that total testosterone levels (P < 0.01) and SHBG (P < 0.01) are independently associated with the occurrence of atherosclerotic CAD in PM. CONCLUSION: We conclude that increased serum testosterone levels and low SHBG in PM women are associated with the development of atherosclerotic cardiovascular risk factors.

Fetal Skeletal Size and Growth are Relevant Biometric Markers in Vitamin D Deficient Mothers: A North East India Prospective Cohort Study.

CONTEXT: The neonatal skeletal outcomes due to maternal Vitamin D deficiency. AIMS: The aim of this study is to assess the serum 25 hydroxy Vitamin D (25[OH]D) status in pregnant women and correlate with cord blood 25(OH)D levels, femur length at 34 weeks gestation, and neonatal anthropometry (birth weight, birth length, and head circumference). SETTINGS AND DESIGN: This was prospective cohort study. SUBJECTS AND METHODS: This study was carried out in 250 healthy primigravida between 18 and 40 years of age in the third trimester of gestation attending the Obstetrics and Gynaecology Department of Gauhati Medical College, Guwahati from December 2012 to December 2015. Dietary assessment of calcium and Vitamin D intake, sunlight exposure among the pregnant mothers and fetal femur length measurements were done. The neonates were followed up at birth for biometric assessment and the estimation of cord 25(OH)D. STATISTICAL ANALYSIS USED: Chi-square test and Pearson correlation were carried out to see the association and correlation between different variables. Statistical significance was set at the 0.05 level. RESULTS: We found low Vitamin D levels (60%) in the majority of pregnant mothers and newborns (62.4%). The mean Vitamin D levels were 17.51 ± 2.24 ng/ml and 14.51 ± 1.8 ng/ml among the low Vitamin D maternal subjects and their new born, respectively. There was a significant association of maternal Vitamin D levels with sun exposure, dietary intake of Vitamin D, serum calcium, serum alkaline phosphatase levels, and serum parathyroid hormone in subjects with low Vitamin D. Fetal femur length and birth length were significantly shorter in mothers with low Vitamin D (P < 0.01). CONCLUSIONS: Maternal hypovitaminosis D was associated with adverse skeletal outcome in neonates.