During the 67th Congress of the German Society of Endocrinology, Professor Stefan Bornstein proposed the concept of the virome as an additional metabolically active gland, underscoring the growing evidence of interactions between hormone systems and infectious agents. This suggests that infectious diseases could potentially serve as triggers for the onset of diabetes and other metabolic disorders, prompting discussions on the potential role of vaccination programs in preventing the spread of these so-called “non-communicable diseases”. If further research corroborates these findings, it could challenge the classification of diabetes and similar conditions as “non-communicable diseases,” presenting a paradoxical scenario.

Bornstein highlighted findings from individuals severely affected by COVID-19 during the pandemic, noting a correlation between the virus and diabetes or pre-metabolic syndrome. He emphasised that SARS-CoV-2 exploits endocrine signalling pathways to invade cells and induce organ damage and inflammation. Furthermore, evidence suggests that infections from coronaviruses and other pathogens like influenza can exacerbate existing metabolic conditions, including diabetes and various endocrine disorders.

SARS-CoV-2’s Impact on Insulin-Secreting Beta Cells

Research conducted during the COVID-19 pandemic revealed a heightened risk of developing type 1 diabetes following SARS-CoV-2 infection. In 2021, Bornstein’s team demonstrated that the virus can infect the insulin-secreting beta cells of the pancreas. Through various analytical techniques, they observed viral infiltration into beta cells among COVID-19 patients, even in the absence of newly diagnosed diabetes. This viral presence, along with indications of necroptotic cell death and immune cell infiltration, suggests a potential link between COVID-19 and metabolic disturbances.

In an October 2020 report, Tim Hollstein, MD, and colleagues documented a case involving a 19-year-old man who developed insulin-dependent diabetes following a SARS-CoV-2 infection. Despite lacking autoantibodies typically associated with type 1 diabetes, the individual presented with diabetic ketoacidosis, indicating a significant impact on glucose metabolism post-infection.

Viruses Generating Insulin-Like Proteins

Recent studies have highlighted the ability of certain viruses to produce insulin-like proteins or hormones, disrupting metabolic processes within the host organism. Antiviral therapies may delay the onset of type 1 diabetes by preserving beta cell function. Additionally, conventional treatments for hormonal imbalances, such as DPP-4 inhibitors and metformin, have shown promise in reducing susceptibility to infections.

Understanding Viruses’ Influence on Metabolic Diseases

Viruses can promote metabolic disorders by influencing critical signalling pathways involved in cell survival, proliferation, and apoptosis and by altering glucose metabolism in infected cells. Enteroviruses and other pathogens have been linked to diabetes onset, suggesting a complex interplay between viral infections and genetic predispositions.

Metabolic Diseases’ Impact on Infection

Conversely, infections like hepatitis C virus (HCV) are associated with a higher risk of type 2 diabetes, particularly among older individuals with a family history of the disease. HCV disrupts glucose regulation by increasing insulin resistance in the liver, affecting glucose uptake and insulin signalling pathways.

Immune System Alterations in Metabolic Conditions

Individuals with obesity, diabetes, or insulin resistance often exhibit changes in innate and adaptive immune functions, including compromised neutrophil activity and altered cytokine secretion in adipose tissue. Moreover, studies have shown delayed immune responses to respiratory viruses in insulin-resistant individuals.

Understanding the intricate relationship between viruses, hormones, and metabolic diseases is crucial for developing effective prevention and treatment strategies for these interconnected health issues.

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NHS England has reached a significant milestone by determining that puberty-suppressing hormones (PSH) will not be provided as a standard treatment option for children and adolescents experiencing gender incongruence/gender dysphoria. This decision was based on insufficient evidence supporting the safety or clinical efficacy of PSH, leading to the conclusion that it should not be routinely offered as a treatment option.

What Are Puberty Blockers?

Puberty-suppressing hormones, often referred to as puberty blockers, are synthetic hormones designed to inhibit the body’s production of natural sex hormones. By doing so, they delay the onset of puberty and the development of secondary sexual characteristics. The primary goal is to alleviate the distress associated with gender dysphoria by reducing the intensity of puberty-related anxiety. It’s important to note that this intervention is physically reversible, meaning that if a young person discontinues treatment, their body will resume its natural physical development based on their sex hormones.

What is Gender Dysphoria?

Gender dysphoria is a term used to describe the psychological distress or discomfort experienced by individuals whose gender identity differs from the sex they were assigned at birth. People with gender dysphoria may experience a strong desire to live as a gender different from the one they were assigned, and they may seek medical interventions such as hormone therapy or gender-affirming surgeries to alleviate their distress and align their physical appearance with their gender identity. Gender dysphoria is recognised as a medical condition by various mental health organisations and is often treated through counselling, hormone therapy, and other forms of gender-affirming care.

Mechanism of Action of Gonadotropin-Releasing Hormone (GnRH) Agonists

Gonadotropin-releasing hormone (GnRH) agonists act as activators of the GnRH receptor, the biological target for gonadotropin-releasing hormone (GnRH). These medications, available in both peptide and small molecule forms, are designed to replicate the action of the hypothalamic neurohormone GnRH. By interacting with the GnRH receptor, they release pituitary hormones, including follicle-stimulating hormone (FSH) and luteinising hormone (LH).

Upon initial administration, GnRH agonists trigger a “flare” response, prompting the release of LH and FSH. However, continued exposure to GnRH agonists leads to desensitisation of the pituitary gland, characterised by downregulation of GnRH receptors. This desensitisation process reduces the secretion of LH and FSH, ultimately inducing a state known as hypogonadotropic hypogonadal anovulation, often referred to as “pseudo menopause” or “medical oophorectomy.”

GnRH agonists effectively suppress gonadal testosterone production, resulting in a significant decrease in circulating testosterone levels. In men, this suppression can reach up to 95%, bringing testosterone levels into the castrate or female range.

GnRH’s mechanism of action hinges on calcium (Ca) and its intracellular receptors, calmodulin and protein kinase C. Physiologically, GnRH stimulates the release of both gonadotropins and increases the mRNA levels of the alpha and beta subunits. Furthermore, GnRH facilitates the terminal glycosylation of LH and FSH.

It seems counterintuitive that stimulating the GnRH agonist leads to a decrease in the secretion of LH and FSH. However, the physiology of this interaction becomes clear when one understands the mechanism. Exposure to pulsatile GnRH leads to an upregulation of receptors, whereas continuous administration of GnRH or GnRH agonists results in receptor loss and pituitary desensitisation. Despite significant advancements, the exact desensitisation process requires further elucidation of post-receptor events.

Drugs Used in the UK

To date, the NHS has prescribed puberty-suppressing hormones after evaluation for children and young individuals diagnosed with persistent gender dysphoria at a specific stage of pubertal development. This prescription typically accompanies psychosocial and psychological support and undergoes review by NHS England’s Multi-Professional Review Group (MPRG).

GnRH analogues such as triptorelin, leuprorelin, and goserelin are utilised in the treatment of gender dysphoria.

According to a 2020 evidence review conducted by NICE, triptorelin holds marketing authorisation in England for managing prostate cancer, endometriosis, and precocious puberty. Its use for children and adolescents with gender dysphoria falls under off-label prescribing.

Leuprorelin, on the other hand, is employed in treating prostate cancer, endometriosis, and premenopausal and perimenopausal breast cancer.

Similarly, goserelin finds application in the treatment of prostate cancer and endometriosis, as well as for endometrial thinning before intrauterine surgery.

Concerns Regarding the use of GnRH analogues for Children with Gender Dysphoria

Currently, there is a significant dearth of robust evidence regarding the effectiveness and long-term ramifications of hormone therapies utilised in addressing gender dysphoria in children.

The Cass Review initiated a thorough examination of available evidence to illuminate the clinical effectiveness, safety, and cost-effectiveness of GnRH analogues in halting puberty for children and young individuals contending with gender dysphoria.

In conducting this review, NICE meticulously scrutinised nine observational studies delving into the clinical efficacy of GnRH analogues and their impact on various outcomes, including gender dysphoria, mental well-being, and quality of life. Additionally, the analysis encompassed effects on body image, bone density, and cognitive function.

Following the review, NICE identified a scarcity of high-quality evidence, leading to low certainty surrounding the outcomes associated with GnRH analogue usage at the time of the assessment. This lack of certainty stemmed from various factors, including unreliable comparative studies on hormone treatments within this context, incomplete reporting of treatment modalities, disparities in outcome measurement approaches, potential biases, confounding variables, and chance influences on study outcomes. Furthermore, the absence of long-term follow-up data exacerbated this uncertainty.

NICE’s evaluation revealed that studies reporting on critical outcomes such as gender dysphoria and mental health indicators—such as depression, anger, and anxiety—as well as significant aspects like body image and psychosocial impact among children and adolescents with gender dysphoria yielded findings of very low certainty. Moreover, the observed changes with GnRH analogues from baseline to follow-up were minimal.

Additionally concerning is the lack of clarity regarding the potential long-term effects of puberty suppression on bone health. Equally ambiguous is the impact of GnRH analogues and puberty interruption on the developmental trajectory of the adolescent brain, and whether any observed effects are entirely reversible remains uncertain.

References:

Davy, Z. and Toze, M., 2018. What is gender dysphoria? A critical systematic narrative review. Transgender health, 3(1), pp.159-169.

Horton, C., 2024. The Cass Review: Cis-supremacy in the UK’s approach to healthcare for trans children. International Journal of Transgender Health, pp.1-25.

Ortmann, O., Weiss, J.M. and Diedrich, K., 2002. Gonadotrophin-releasing hormone (GnRH) and GnRH agonists: mechanisms of action. Reproductive biomedicine online, 5, pp.1-7.

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In the study, the blood test demonstrated a success rate of 83% in identifying cancers. Still, it fell short in detecting most precancerous growths typically detected by colonoscopy, the gold standard for colon cancer screening. Colonoscopies detect tumours and play a crucial role in preventing the disease by removing precancerous growths known as polyps.

Despite colonoscopy’s effectiveness in identifying cancer and precancerous growths, many individuals are deterred from undergoing the procedure due to the inconvenience of taking time off work and the bowel preparation involved, which includes the consumption of a laxative. As a more convenient alternative, annual stool tests allow individuals to submit samples to a lab for analysis.

Colon cancer screening is recommended for healthy adults aged 45 to 75 at average risk, with the screening frequency depending on the chosen test. While routine colonoscopies are recommended every ten years, Guardant suggests testing with its blood test called Shield every three years. However, similar to stool tests, an abnormal result from the blood test necessitates a follow-up colonoscopy, potentially leading to additional out-of-pocket expenses.

The study, funded by Guardant and published in the New England Journal of Medicine, involved 7,861 participants who underwent both a colonoscopy and a blood test. While the blood test successfully detected 83% of the cancers identified by colonoscopy, it missed detection in 17% of cases, placing it on par with stool-based tests.

Notably, the study also uncovered several false positives, falsely indicating cancer in 10% of cases, which were not confirmed by subsequent colonoscopies. This underscores the necessity for further research to determine if the blood test may detect other cancers and produce misleading results.

Colorectal cancer ranks as the second leading cause of cancer deaths in the United States and the third worldwide. With over 153,000 new cases and 53,000 deaths expected this year in the US alone, enhanced screening efforts have the potential to reduce mortality rates associated with the disease.

Dr. Nabil Mansour of Baylor College of Medicine expressed optimism about having a reliable blood test option for colon cancer screening. While he will continue to recommend colonoscopies for his patients, having an alternative screening method offers greater flexibility and accessibility in detecting and preventing colon cancer.

In conclusion, the development of innovative screening methods, such as the blood test for colon cancer, signifies a significant stride in combating this deadly disease. By offering a range of screening options, healthcare providers can empower individuals to take proactive measures toward protecting their health and well-being.

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