Long-Term Gynecological Outcomes in Women with Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency

Background. Our knowledge on long-term outcome in CAH remains incomplete. Methods. In a prospective study (33 CAH patients, 33 age-matched controls), reproductive outcomes, self-rating of genital appearance and function, and sexuality were correlated to degree of initial virilisation, genotype, and surgery. Results. Patients had larger median clitoral lengths (10.0 mm [range 2–30] versus 3.5 [2–8], P < .001), shorter vaginal length (121 mm [100–155] versus 128 [112–153], P = .12), lower uterine volumes (29.1 ml [7.5–56.7] versus 47.4 [15.9–177.5], P = .009), and higher ovarian volumes (4.4 ml [1.3–10.8] versus 2.8 [0.6–10.8], P = .09) than controls. Satisfaction with genital appearance was lower and negatively correlated to degree of initial virilisation (rs = ≤−0.39, P ≤ .05). More patients had never had intercourse (P = .001), and age at 1st intercourse was higher (18 yrs versus 16 yrs, P = .02). Conclusion. Despite overall acceptable cosmetic results, reproductive outcomes were suboptimal, supporting that multidisciplinary teams should be involved in adult follow up of CAH patients

Differential impact of glucose administered intravenously and orally on circulating mir-375 levels in human subjects

Background: To date, numerous nucleic acid species have been detected in the systemic circulation including microRNAs (miRNAs); however their functional role in this compartment remains unclear. Objective: The aim of this study was to determine whether systemic levels of miRNAs abundant in blood, including the neuroendocrine tissue-enriched miR-375, are altered in response to a glucose challenge. Design: Twelve healthy males were recruited for an acute cross-over study which consisted of two tests each following an eight-hour fasting period. An oral glucose tolerance test (OGTT) was performed and blood samples were collected over a 3-hour period. Following a period of at least one week, the same participants were administered an isoglycemic intravenous glucose infusion (IIGI) with the same blood collection protocol. Results: The glucose response curve following the IIGI mimicked that obtained after the OGTT, but as expected systemic insulin levels were lower during the IIGI compared to the OGTT (P<0.05). MiR-375 levels in circulation were increased only in response to an OGTT and not during an IIGI. In addition, the response to the OGTT also coincided with the transient increase of circulating glucagon-like peptide-1 (GLP-1), glucagon-like peptide-2 (GLP-2), and glucose-dependent insulinotropic polypeptide (GIP). Conclusions: The present findings show levels of miR-375 increase following administration of an OGTT and in light of its enrichment in cells of the gut, suggest that the gastrointestinal tract may play a significant role to the abundance and function of this microRNA in the blood

Treatment with insulin (analogues) and breast cancer risk in diabetics; a systematic review and meta-analysis of in vitro, animal and human evidence

INTRODUCTION: Several studies have suggested that anti-diabetic insulin analogue treatment might increase cancer risk. The aim of this study was to review the postulated association between insulin and insulin analogue treatment and breast cancer development, and plausible mechanisms. METHOD: A systematic literature search was performed on breast cell-line, animal and human studies using the key words 'insulin analogue' and 'breast neoplasia' in MEDLINE at PubMed, EMBASE, and ISI Web of Science databases. A quantitative and qualitative review was performed on the epidemiological data; due to a limited number of reported estimates, a meta-analysis was performed for glargine only. A comprehensive overview was composed for in vitro and animal studies. Protein and gene expression was analysed for the cell lines most frequently used in the included in vitro studies. RESULTS: In total 16 in vitro, 5 animal, 2 in vivo human and 29 epidemiological papers were included. Insulin AspB10 showed mitogenic properties in vitro and in animal studies. Glargine was the only clinically available insulin analogue for which an increased proliferative potential was found in breast cancer cell lines. However, the pooled analysis of 13 epidemiological studies did not show evidence for an association between insulin glargine treatment and an increased breast cancer risk (HR 1.04; 95 % CI 0.91-1.17; p=0.49) versus no glargine in patients with diabetes mellitus. It has to be taken into account that the number of animal studies was limited, and epidemiological studies were underpowered and suffered from methodological limitations. CONCLUSION: There is no compelling evidence that any clinically available insulin analogue (Aspart, Determir, Glargine, Glulisine or Lispro), nor human insulin increases breast cancer risk. Overall, the data suggests that insulin treatment is not involved in breast tumour initiation, but might induce breast tumour progression by up regulating mitogenic signalling pathways

Can ChatGPT outperform a neurosurgical trainee? A prospective comparative study

Purpose This study aimed to compare the performance of ChatGPT, a large language model (LLM), with human neurosurgical applicants in a neurosurgical national selection interview, to assess the potential of artificial intelligence (AI) and LLMs in healthcare and provide insights into their integration into the field. Methods In a prospective comparative study, a set of neurosurgical national selection-style interview questions were asked to eight human participants and ChatGPT in an online interview. All participants were doctors currently practicing in the UK who had applied for a neurosurgical National Training Number. Interviews were recorded, anonymised, and scored by three neurosurgical consultants with experience as interviewers for national selection. Answers provided by ChatGPT were used as a template for a virtual interview. Interview transcripts were subsequently scored by neurosurgical consultants using criteria utilised in real national selection interviews. Overall interview score and subdomain scores were compared between human participants and ChatGPT. Results For overall score, ChatGPT fell behind six human competitors and did not achieve a mean score higher than any individuals who achieved training positions. Several factors, including factual inaccuracies and deviations from expected structure and style may have contributed to ChatGPT's underperformance. Conclusions LLMs such as ChatGPT have huge potential for integration in healthcare. However, this study emphasises the need for further development to address limitations and challenges. While LLMs have not surpassed human performance yet, collaboration between humans and AI systems holds promise for the future of healthcare

Glucose Tolerance Tests and Osteocalcin Responses in Healthy People

Aim: Osteocalcin and undercarboxylated osteocalcin are suggested to be endocrine messengers from the bones and have been shown to stimulate insulin secretion from pancreatic β-cells. Insulin is hypothesized to increase the osteoblastic production of osteocalcin. The aim of the study was to investigate whether the route of glucose administration influence the circulating levels of osteocalcin and undercarboxylated osteocalcin.Methods: Twelve healthy males were enrolled in an acute cross-over study where they underwent an oral glucose tolerance test (OGTT), an isoglycemic intravenous glucose infusion (IIGI) and a fasting period (control). Blood samples were collected throughout 180 min and analyzed for osteocalcin and undercarboxylated osteocalcin and compared to insulin, glucose, and gastro-intestinal hormone responses.Results: Neither osteocalcin levels nor undercarboxylated osteocalcin levels over time differed between the OGTT, IIGI, and fasting. Baseline insulin levels and glucose levels were not associated with osteocalcin or undercarboxylated osteocalcin levels. Increases in insulin and glucose levels were neither associated with altered osteocalcin nor undercarboxylated osteocalcin levels.Conclusion: The route of glucose administration does not influence the circulating levels of osteocalcin and undercarboxylated osteocalcin despite the differential insulin and incretin responses. In the acute setting this suggests that insulin does not increase osteoblastic production of osteocalcin in healthy human males

Obesity, Type 2 Diabetes and Bone in Adults.

In an increasingly obese and ageing population, type 2 diabetes (T2DM) and osteoporotic fracture are major public health concerns. Understanding how obesity and type 2 diabetes modulate fracture risk is important to identify and treat people at risk of fracture. Additionally, the study of the mechanisms of action of obesity and T2DM on bone has already offered insights that may be applicable to osteoporosis in the general population. Most available evidence indicates lower risk of proximal femur and vertebral fracture in obese adults. However the risk of some fractures (proximal humerus, femur and ankle) is higher, and a significant number fractures occur in obese people. BMI is positively associated with BMD and the mechanisms of this association in vivo may include increased loading, adipokines such as leptin, and higher aromatase activity. However, some fat depots could have negative effects on bone; cytokines from visceral fat are pro-resorptive and high intramuscular fat content is associated with poorer muscle function, attenuating loading effects and increasing falls risk. T2DM is also associated with higher bone mineral density (BMD), but increased overall and hip fracture risk. There are some similarities between bone in obesity and T2DM, but T2DM seems to have additional harmful effects and emerging evidence suggests that glycation of collagen may be an important factor. Higher BMD but higher fracture risk presents challenges in fracture prediction in obesity and T2DM. Dual energy X-ray absorptiometry underestimates risk, standard clinical risk factors may not capture all relevant information, and risk is under-recognised by clinicians. However, the limited available evidence suggests that osteoporosis treatment does reduce fracture risk in obesity and T2DM with generally similar efficacy to other patients

Treatment with insulin (analogues) and breast cancer risk in diabetics; a systematic review and meta-analysis of in vitro, animal and human evidence

INTRODUCTION: Several studies have suggested that anti-diabetic insulin analogue treatment might increase cancer risk. The aim of this study was to review the postulated association between insulin and insulin analogue treatment and breast cancer development, and plausible mechanisms. METHOD: A systematic literature search was performed on breast cell-line, animal and human studies using the key words 'insulin analogue' and 'breast neoplasia' in MEDLINE at PubMed, EMBASE, and ISI Web of Science databases. A quantitative and qualitative review was performed on the epidemiological data; due to a limited number of reported estimates, a meta-analysis was performed for glargine only. A comprehensive overview was composed for in vitro and animal studies. Protein and gene expression was analysed for the cell lines most frequently used in the included in vitro studies. RESULTS: In total 16 in vitro, 5 animal, 2 in vivo human and 29 epidemiological papers were included. Insulin AspB10 showed mitogenic properties in vitro and in animal studies. Glargine was the only clinically available insulin analogue for which an increased proliferative potential was found in breast cancer cell lines. However, the pooled analysis of 13 epidemiological studies did not show evidence for an association between insulin glargine treatment and an increased breast cancer risk (HR 1.04; 95 % CI 0.91-1.17; p=0.49) versus no glargine in patients with diabetes mellitus. It has to be taken into account that the number of animal studies was limited, and epidemiological studies were underpowered and suffered from methodological limitations. CONCLUSION: There is no compelling evidence that any clinically available insulin analogue (Aspart, Determir, Glargine, Glulisine or Lispro), nor human insulin increases breast cancer risk. Overall, the data suggests that insulin treatment is not involved in breast tumour initiation, but might induce breast tumour progression by up regulating mitogenic signalling pathways.Toxicolog

Treatment with insulin (analogues) and breast cancer risk in diabetics; a systematic review and meta-analysis of in vitro, animal and human evidence

INTRODUCTION: Several studies have suggested that anti-diabetic insulin analogue treatment might increase cancer risk. The aim of this study was to review the postulated association between insulin and insulin analogue treatment and breast cancer development, and plausible mechanisms. METHOD: A systematic literature search was performed on breast cell-line, animal and human studies using the key words 'insulin analogue' and 'breast neoplasia' in MEDLINE at PubMed, EMBASE, and ISI Web of Science databases. A quantitative and qualitative review was performed on the epidemiological data; due to a limited number of reported estimates, a meta-analysis was performed for glargine only. A comprehensive overview was composed for in vitro and animal studies. Protein and gene expression was analysed for the cell lines most frequently used in the included in vitro studies. RESULTS: In total 16 in vitro, 5 animal, 2 in vivo human and 29 epidemiological papers were included. Insulin AspB10 showed mitogenic properties in vitro and in animal studies. Glargine was the only clinically available insulin analogue for which an increased proliferative potential was found in breast cancer cell lines. However, the pooled analysis of 13 epidemiological studies did not show evidence for an association between insulin glargine treatment and an increased breast cancer risk (HR 1.04; 95 % CI 0.91-1.17; p=0.49) versus no glargine in patients with diabetes mellitus. It has to be taken into account that the number of animal studies was limited, and epidemiological studies were underpowered and suffered from methodological limitations. CONCLUSION: There is no compelling evidence that any clinically available insulin analogue (Aspart, Determir, Glargine, Glulisine or Lispro), nor human insulin increases breast cancer risk. Overall, the data suggests that insulin treatment is not involved in breast tumour initiation, but might induce breast tumour progression by up regulating mitogenic signalling pathways.Toxicolog

Treatment with insulin (analogues) and breast cancer risk in diabetics; a systematic review and meta-analysis of in vitro, animal and human evidence

INTRODUCTION: Several studies have suggested that anti-diabetic insulin analogue treatment might increase cancer risk. The aim of this study was to review the postulated association between insulin and insulin analogue treatment and breast cancer development, and plausible mechanisms. METHOD: A systematic literature search was performed on breast cell-line, animal and human studies using the key words 'insulin analogue' and 'breast neoplasia' in MEDLINE at PubMed, EMBASE, and ISI Web of Science databases. A quantitative and qualitative review was performed on the epidemiological data; due to a limited number of reported estimates, a meta-analysis was performed for glargine only. A comprehensive overview was composed for in vitro and animal studies. Protein and gene expression was analysed for the cell lines most frequently used in the included in vitro studies. RESULTS: In total 16 in vitro, 5 animal, 2 in vivo human and 29 epidemiological papers were included. Insulin AspB10 showed mitogenic properties in vitro and in animal studies. Glargine was the only clinically available insulin analogue for which an increased proliferative potential was found in breast cancer cell lines. However, the pooled analysis of 13 epidemiological studies did not show evidence for an association between insulin glargine treatment and an increased breast cancer risk (HR 1.04; 95 % CI 0.91-1.17; p=0.49) versus no glargine in patients with diabetes mellitus. It has to be taken into account that the number of animal studies was limited, and epidemiological studies were underpowered and suffered from methodological limitations. CONCLUSION: There is no compelling evidence that any clinically available insulin analogue (Aspart, Determir, Glargine, Glulisine or Lispro), nor human insulin increases breast cancer risk. Overall, the data suggests that insulin treatment is not involved in breast tumour initiation, but might induce breast tumour progression by up regulating mitogenic signalling pathways.Toxicolog

Premature ovarian failure and ovarian autoimmunity

Premature ovarian failure (POF) is defined as a syndrome characterized by menopause before the age of 40 yr. The patients suffer from anovulation and hypoestrogenism. Approximately 1% of women will experience menopause before the age of 40 yr. POF is a heterogeneous disorder with a multicausal pathogenesis involving chromosomal, genetic, enzymatic, infectious, and iatrogenic causes. There remains, however, a group of POF patients without a known etiology, the so-called "idiopathic" form. An autoimmune etiology is hypothesized for the POF cases with a concomitant Addison's disease and/or oophoritis. It is concluded in this review that POF in association with adrenal autoimmunity and/or Addison's disease (2-10% of the idiopathic POF patients) is indeed an autoimmune disease. The following evidence warrants this view: 1) The presence of autoantibodies to steroid-producing cells in these patients; 2) The characterization of shared autoantigens between adrenal and ovarian steroid-producing cells; 3) The histological picture of the ovaries of such cases (lymphoplasmacellular infiltrate around steroid-producing cells); 4) The existence of various autoimmune animal models for this syndrome, which underlines the autoimmune nature of the disease. There is some circumstantial evidence for an autoimmune pathogenesis in idiopathic POF patients in the absence of adrenal autoimmunity or Addison's disease. Arguments in support of this are: 1) The presence of cellular immune abnormalities in this POF patient group reminiscent of endocrine autoimmune diseases such as IDDM, Graves' disease, and Addison's disease; 2) The more than normal association with IDDM and myasthenia gravis. Data on the presence of various ovarian autoantibodies and anti-receptor antibodies in these patients are, however, inconclusive and need further evaluation. A strong argument against an autoimmune pathogenesis of POF in these patients is the nearly absent histological confirmation (the presence of an oophoritis) in these cases (< 3%). However, in animal models using ZP immunization, similar follicular depletion and fibrosis (as in the POF women) can be detected. Accepting the concept that POF is a heterogenous disorder in which some of the idiopathic forms are based on an abnormal self-recognition by th