The maintenance of long-term weight loss after semaglutide withdrawal in obese women with PCOS treated with metformin: a 2-year observational study.

Background: Withdrawal of semaglutide is frequently followed by weight regain due to compensatory biological changes that prevent the maintenance of long-term weight loss. There are some studies implying that metformin might attenuate weight regain. The weight trajectory after discontinuation of short-term semaglutide treatment in obese women with PCOS who continued metformin treatment has not yet been evaluated. Aims: We explored changes in body weight, cardiometabolic and endocrine parameters in obese women with PCOS who continued treatment with metformin 2 years after discontinuation of short-term intervention with semaglutide. Methods: 25 women with PCOS and obesity, aged 33.7 ± 5.3 years (mean ± SD), were treated with once-weekly subcutaneous semaglutide 1.0 mg as an adjunct to metformin 2000 mg/day and lifestyle intervention for 16 weeks. At week 16, semaglutide was discontinued. Treatment with metformin 2000 mg/day and promotion of lifestyle intervention were continued during the 2-year follow-up period. Weight change, cardiometabolic, and endocrine parameters were assessed 2 years after semaglutide discontinuation. Results: During semaglutide treatment phase, weight decreased from 101 (90-106.8) kg to 92 (83.3-100.8) kg. Two years after semaglutide withdrawal, weight was 95 (77-104) kg. The net weight loss 2 years after discontinuation of semaglutide remained significant when compared to baseline (p=0.003). At the end of the study, 21 out of 25 subjects had lower body weight compared to baseline. Improvements in cardiometabolic parameters including decrease in total and LDL cholesterol, fasting glucose, and glucose after OGTT that had been seen during semaglutide-treatment phase reverted towards baseline two years after semaglutide cessation. Free testosterone levels significantly decreased during semaglutide treatment from 6.16 (4.07-9.71) to 4.12 (2.98-6.93) nmol/l, (p= 0.012) and did not significantly deteriorate after semaglutide discontinuation. Conclusion: Two years after semaglutide withdrawal, women with PCOS who continued with metformin regained about one-third of the semaglutide-induced weight loss. At the end of the follow up, 84% of women had a lower body weight than at baseline.

The Current and Emerging Role of Statins in the Treatment of PCOS: The Evidence to Date.

Polycystic ovary syndrome (PCOS) manifests a multifactorial pathology characterized by polycystic ovaries, menstrual cycle disorders, varying degrees of hyperandrogenism, and an ad-verse metabolic risk profile. The position of hyperandrogenism in this syndrome has been extensively studied. A multitude of mechanisms place it in the position of cause but also of consequence; therefore, ongoing research efforts are focused on identifying medications that can effectively reduce levels of androgens in women with PCOS. Moreover, lipid abnormalities are common in this population, with up to 70% of patients having dyslipidemia. Statins may have potential therapeutic benefits for women with PCOS, as they have been shown to improve insulin resistance and reduce the risk of cardiovascular disease. In addition, their role in accelerated steroidogenesis by limiting one source of cholesterol, influencing enzymatic activity, and providing several other beneficial mechanisms is widely investigated. This review aimed to provide a comprehensive overview of the pathogenesis of androgen excess and dyslipidemia in PCOS, as well as the therapeutic potential of statins.

Hyperparathyroidism and Peripheral Arterial Disease.

Primary hyperparathyroidism (PHPT) is presented in various forms, including classic PHPT, characterised by increased parathyroid hormone (PTH) secretion, normohormonal PHPT, and normocalcaemic PHPT. Secondary hyperparathyroidism is characterised by increased PTH secretion triggered by factors such as vitamin D deficiency and kidney failure. This review aims to discuss the involvement of hyperparathyroidism (HPT) in atherosclerosis, including peripheral arterial disease (PAD). The increased level of PTH is involved in developing subclinical and overt vascular diseases, encompassing endothelial dysfunction, vascular stiffness, hypertension, and coronary and peripheral arterial diseases. It has been consistently associated with an augmented risk of cardiovascular morbidity and mortality, independent of classical risk factors for atherosclerosis. Chronic hypercalcemia associated with increased levels of PTH contributes to the development of calcification of vessel walls and atherosclerotic plaques. Vascular calcification can occur in the intima or media of the arterial wall and is associated with stiffness of peripheral arteries, which the formation of atherosclerotic plaques and narrowing of the vessel lumen can follow. For treating hyperparathyroidism, particularly SHPT, calcimimetics, novel phosphorus binders and novel vitamin D receptor activators are used. However, they are ineffective in severe PHPT. Therefore, parathyroidectomy remains the primary therapeutic option of PHPT.

Thyroid Disorders and Peripheral Arterial Disease.

Hypothyroidism and hyperthyroidism, both overt and subclinical, are associated with increased risk of cardiovascular morbidity and mortality. The association between thyroid-stimulating hormone levels and cardiovascular risk has been demonstrated in large epidemiological studies and meta-analyses and is now considered a U-shaped curve. Several pathophysiological mechanisms linking thyroid and cardiovascular disease are known; however, specific clinical complications of peripheral arterial disease as endpoints of clinical trials have not been adequately investigated. The potential mechanisms linking hypothyroidism and peripheral arterial disease are endothelial dysfunction, blood pressure changes, dyslipidemia, and low-grade systemic inflammation. The potential mechanisms linking hyperthyroidism and peripheral arterial disease are hyperdynamic circulation, elevated systolic blood pressure, hypercoagulability, and possibly increased arterial inflammation.

Prolactin in Polycystic Ovary Syndrome: Metabolic Effects and Therapeutic Prospects.

Polycystic ovary syndrome (PCOS) is the most prevalent endocrine and metabolic disorder in premenopausal women, characterized by hyperandrogenism, ovulatory dysfunction, and polycystic ovaries. Patients frequently present comorbidities, including obesity, insulin resistance, and impaired glucose and lipid metabolism. The diverse clinical presentation may mimic various endocrine disorders, making the diagnosis challenging in some clinical circumstances. Prolactin (PRL) is a recommended biomarker in the initial diagnostic workup to rule out hyperprolactinemia (HPRL). The traditional role of PRL is linked to lactation and the reproductive system. Recent research highlights PRL's emerging role in metabolic homeostasis. PRL influences metabolism directly by interacting with the pancreas, liver, hypothalamus, and adipose tissue. Its influence on an individual's metabolism is intricately tied to its serum concentration. While deficient and very high levels of PRL can negatively affect metabolism, intermediate-normal to moderately high levels may promote metabolic health. In women with PCOS, PRL levels may be altered. Research results on different aspects of the relationship between PCOS and the impact of various levels of PRL on metabolic homeostasis are limited and inconsistent. In this narrative literature review, we comprehensively examined data on serum PRL levels in PCOS patients. We investigated the correlation between a favorable metabolic profile and serum PRL levels in this population. Furthermore, we explored the concept of beneficial PRL effects on metabolism and discussed the potential therapeutic application of dopamine agonists in PCOS treatment. Lastly, we emphasized several promising avenues for future research in this field.

Case Report: Multiple prolactinomas in a young man with Kallmann syndrome and familial hypocalciuric hypercalcemia.

Introduction: The occurrence of prolactinomas in sex hormone treated patients with central hypogonadism is extremely rare. Case presentation: We present a Caucasian male patient who was diagnosed with Kallmann syndrome (KS) at age 15 years. Testosterone treatment was started. At age 26 the patient presented with mild headache. MRI revealed two separate pituitary adenomas along with the absence of the olfactory bulbs. Given the presence of marked hyperprolactinemia (17x upper limit of the reference range) the diagnosis prolactinoma was made and treatment with cabergoline was started which resulted in a complete biochemical response and in marked reduction of both adenomas in size. Hypogonadism persisted and testosterone replacement therapy was continued. Genetic testing of genes associated with pituitary tumors, Kallmann syndrome and idiopathic hypogonadotropic hypogonadism was negative. Mild concomitant hypercalcemia in accordance with familial hypocalciuric hypercalcemia (FHH) prompted mutation analysis of the calcium receptor (CASR) gene which yielded a pathogenic inactivating variant. Discussion/conclusion: The presence of two separate prolactinomas in a patient with KS has not yet been reported in the literature. The effect of sex hormone treatment of KS patients on the possible development of prolactinoma is unknown at present. The occurance of multiple prolactinomas in our patient suggests increased susceptibility. Although CaSR is expressed in GnRH neurons in mouse brain and CaSR deficient mice have a reduced hypothalamic GnRH neuronal population, the relevance of the CASR gene variant in our patient for the KS phenotype is unclear at present.

The Effect of Menopause and Menopausal Hormone Therapy on the Risk of Peripheral Artery Disease.

Peripheral artery disease (PAD), defined as lower extremity arterial disease, constitutes an underestimated aspect of the menopause-associated risk of atherosclerotic cardiovascular disease (ASCVD). Accumulation of ASCVD risk factors, such as atherogenic dyslipidaemia, diabetes, and arterial hypertension, after the transition to menopause may contribute to atherosclerotic plaque formation in peripheral arteries. However, inconsistency exists among studies as to whether transition to menopause increases the risk of PAD, although early menopause (<45 years) or premature ovarian insufficiency may accelerate peripheral atherosclerotic plaque formation. Menopausal hormone therapy may decrease the risk of PAD if administered early (i.e., within the first 5-6 years after last menstruation), whereas it has no effect in women with established ASCVD.

Cardiometabolic Risk, Peripheral Arterial Disease and Cardiovascular Events in Polycystic Ovary Syndrome: Time to Implement Systematic Screening and Update the Management.

Polycystic ovary syndrome (PCOS) is a highly prevalent endocrine disorder in women of reproductive age. It presents with gynaecologic, metabolic, and psychologic manifestations. The dominant drivers of pathophysiology are hyperandrogenism and insulin resistance. Both conditions are related to cardiometabolic risk factors, such as obesity, hypertension, dyslipidaemia, hyperglycaemia, type 2 and gestational diabetes, nonalcoholic fatty liver disease and obstructive sleep apnoea. Women with PCOS of reproductive age consistently demonstrated an elevated risk of subclinical atherosclerosis, as indicated by different measurement methods, while findings for menopausal age groups exhibited mixed results. Translation of subclinical atherosclerosis into the increased incidence of peripheral arterial disease and major cardiovascular (CV) events is less clear. Although several expert groups have advised screening, the CV risk assessment and prevention of CV events are frequently underdiagnosed and overlooked aspects of the management of PCOS. A combination of lifestyle management and pharmacotherapy, including the promising new era of anti-obesity medicine, can lead to improvements in cardiometabolic health.

Testosterone and Peripheral Arterial Disease.

Testosterone levels in men begin declining in the early years of adulthood, with a 1-2% reduction/year. Low testosterone levels in men are associated with obesity, metabolic syndrome, diabetes mellitus, dyslipidaemia, hypertension and increased cardiovascular mortality. However, observational studies of testosterone levels in males and their relationship with peripheral arterial disease (PAD) have yielded mixed results; only some cohorts show a clear association with low free testosterone levels. This discrepancy may, in part, be due to methodological issues with estimating free testosterone but also to different effects of testosterone on the vessel wall and metabolism. While testosterone improves glycaemic control, has anti-obesity effects and induces vasodilation, it also stimulates platelet aggregation and increases the haematocrit. Androgen deprivation treatment for advanced prostate cancer may be associated with elevated cardiovascular risk, as is testosterone abuse for performance enhancement. On the other hand, judicious treatment of male hypogonadism or testosterone treatment of trans-men appears to be safe.

Brown Adipose Tissue: A New Potential Target for Glucagon-like Peptide 1 Receptor Agonists in the Treatment of Obesity.

Adipose tissue can be divided into white adipose tissue (WAT), brown adipose tissue (BAT), and beige adipose tissue, according to the differences in morphology. WAT acts as a buffer for increased energy intake and decreased energy expenditure during the development of obesity, resulting in visceral and ectopic WAT accumulation. These WAT depots are strongly associated with chronic systemic inflammation, insulin resistance, and cardiometabolic risk related to obesity. They represent a primary weight loss target in anti-obesity management. Second-generation anti-obesity medications glucagon-like peptide-1 receptor agonists (GLP-1RAs) cause weight loss and improve body composition by reducing visceral and ectopic fat depots of WAT, resulting in improved cardiometabolic health. Recently, the understanding of the physiological significance of BAT beyond its primary function in generating heat through non-shivering thermogenesis has been expanded. This has raised scientific and pharmaceutical interest in the manipulation of BAT to further enhance weight reduction and body weight maintenance. This narrative review focuses on the potential impact of GLP-1 receptor agonism on BAT, particularly in human clinical studies. It provides an overview of the role of BAT in weight management and highlights the need for further research to elucidate the mechanisms by which GLP-1RAs affect energy metabolism and weight loss. Despite encouraging preclinical data, limited clinical evidence supports the notion that GLP-1RAs contribute to BAT activation.

Effects of Mindfulness-Based Therapy on Clinical Symptoms and DNA Methylation in Patients with Polycystic Ovary Syndrome and High Metabolic Risk.

Polycystic ovary syndrome (PCOS) is an endocrine and metabolic disorder affecting women of reproductive age. Research has shown that epigenetic alterations such as DNA methylation may play a role in the development and progression of abnormal ovarian function and metabolic disorders in PCOS. Studies have identified specific genes (related with insulin signaling and steroid hormone metabolism) that are methylated in women with PCOS. DNA methylation appears to respond to various interventions aimed at altering health and lifestyle factors. We tested the efficacy of a mindfulness-based stress reduction program (MBSR) in PCOS patients. We examined its effects on anthropometric measurements, mental health and wellbeing, and alterations in DNA methylation in peripheral blood. MBSR was associated with a reduction in body mass index, waist circumference and blood glucose level, an improvement in subjectively perceived general health, emotional role limitation, and levels of pain, as well as mindfulness-like traits. MBSR reduced the expression of anxious symptomatology and subjectively perceived stress. Methylation changes were observed in four genes: COMT, FST, FKBP51, and MAOA. We conclude that MBSR may be a useful supplementary therapy to mitigate the deleterious effects of PCOS on mental health.

Insulin Metabolism in Polycystic Ovary Syndrome: Secretion, Signaling, and Clearance.

Polycystic ovary syndrome (PCOS) is the most common endocrine and metabolic disorder in women of reproductive age. Its heterogeneous clinical presentation is characterized by hyperandrogenemia, reproductive changes, polycystic ovary morphology, and insulin resistance (IR). The primary pathophysiological process in its multifactorial etiology has not yet been identified. However, the two most proposed core etiologies are the disruption of insulin metabolism and hyperandrogenemia, both of which begin to intertwine and propagate each other in the later stages of the disease. Insulin metabolism can be viewed as the interconnectedness of beta cell function, IR or insulin sensitivity, and insulin clearance. Previous studies of insulin metabolism in PCOS patients have yielded conflicting results, and literature reviews have focused mainly on the molecular mechanisms and clinical implications of IR. In this narrative review, we comprehensively explored the role of insulin secretion, clearance, and decreased sensitivity in target cells as a potential primary insult in PCOS pathogenesis, along with the molecular mechanism behind IR in PCOS.

Semaglutide delays 4-hour gastric emptying in women with polycystic ovary syndrome and obesity.

AIM: To evaluate the effect of once-weekly subcutaneous semaglutide 1.0 mg on the late digestive period of gastric emptying (GE) after ingestion of a standardized solid test meal by using technetium scintigraphy, the reference method for this purpose. METHODS: We conducted a single-blind, placebo-controlled trial in 20 obese women with polycystic ovary syndrome (PCOS; mean [range] age 35 [32.3-40.8] years, body mass index 37 [30.7-39.8] kg/m2 ) randomized to subcutaneous semaglutide 1.0 mg once weekly or placebo for 12 weeks. GE was assessed after ingestion of [99mT c] colloid in a pancake labelled with radiopharmaceutical by scintigraphy using sequential static imaging and dynamic acquisition at baseline and at Week 13. Estimation of GE was obtained by repeated imaging of remaining [99mT c] activity at fixed time intervals over the course of 4 hours after ingestion. RESULTS: From baseline to the study end, semaglutide increased the estimated retention of gastric contents by 3.5% at 1 hour, 25.5% at 2 hours, 38.0% at 3 hours and 30.0% at 4 hours after ingestion of the radioactively labelled solid meal. Four hours after ingestion, semaglutide retained 37% of solid meal in the stomach compared to no gastric retention in the placebo group (P = 0.002). Time taken for half the radiolabelled meal to empty from the stomach was significantly longer in the semaglutide group than the placebo group (171 vs. 118 min; P < 0.001). CONCLUSION: Semaglutide markedly delayed 4-hour GE in women with PCOS and obesity.

Glucagon-Like Peptide-1 Receptor Agonists in the Treatment of Obesity.

BACKGROUND: Obesity treatment based on glucagon-like peptide-1 receptor agonists (GLP-1 RAs) proved to limit morbidity and mortality in adult population. In children, optimizing lifestyle intervention (LSI) and reducing culpable environmental exposures represent the mainstay strategy for obesity prevention and management. However, there remains a subset of children and adolescents whose obesity is resistant to lifestyle approach. For these poor responders, the need for safe and effective weight-reducing agents is apparent. The purpose of this review is to provide an overview of the efficacy and safety of approved GLP-1 RA in the management of adult and pediatric obesity. SUMMARY: We presented the main outcomes of clinical trial programs called SCALE and STEP that supported a market authorization approval for liraglutide and semaglutide for the treatment of obesity in adult population. Then, we summarized the studies on the efficacy of GLP-1 RA in pediatric obesity that have been accumulating from 2 larger studies with liraglutide and few other smaller studies with exenatide and liraglutide. The results indicate that GLP-1 RA is safe, tolerable, and effective in reducing weight and also in improving cardiometabolic profile in children with obesity and poor response to LSI alone. At present, liraglutide is the first and so far the only GLP-1 RA that received FDA approval in 2020 for use in children aged 12-17 years with obesity. New trials including semaglutide for pediatric obesity are ongoing. KEY MESSAGES: There is a strong interest in current use and further development of obesity treatments based on glucagon-like peptide-1 (GLP-1) agonism. In adolescents with obesity, who are poor responders to lifestyle approach, the use of GLP-1 RA as an adjunct to LSI is effective and safe. Due to limited experience, a general recommendation is to prioritize long acting over short acting GLP-1 RA because they are approved for the treatment of obesity and have better tolerability, safety, and treatment response effect. In the future research, more high-grade evidence including novel iterations of GLP-1 agonism and long-term follow-ups are needed in pediatric population.

Impact of COVID-19 Pandemic on Disease Control Status and Quality of Life of Patients with Acromegaly.

Background and Objectives: Despite the best efforts of healthcare workers and the deployment of alternative healthcare delivery solutions through telemedicine, the pandemic has disrupted standard care for patients with chronic conditions. The long-lasting pandemic has also had a profound impact on the quality of life (QoL) of the majority of patients with chronic illnesses. The management of rare diseases has been particularly challenging. We aimed to evaluate the impacts that the long-lasting pandemic had on the disease control status and QoL in patients with acromegaly. Materials and Methods: Our prospective study included 34 patients from a national referral centre. The baseline SAGIT and AcroQoL results were obtained in October 2020 during the lockdown period of the SARS-CoV2 pandemic. The follow-up results were assessed during the summer of 2022 in a period without any public health restrictions. All the patients were additionally evaluated for their attitude towards preventative public health measures against SARS-CoV2 spread and required mask wearing during the pandemic. Results: By comparing assessments in 2020 during the lockdown period and 2022 post-lockdown, we observed some improvement in SAGIT subscores T and I, most likely reflecting treatment changes in a small number of patients. The global SAGIT score remained stable. QoL measurement by AcroQoL did not demonstrate any changes. There was a negative correlation between SAGIT subscore S and the AcroQoL results. We also noted that the group of patients with the most negative attitude toward public health measurements for preventing SARS-CoV2 spread had higher AcroQoL results than others. Conclusion: Our results showcase that the SARS-CoV2 pandemic, lasting over two years, did not impact the disease control status and QoL in patients with acromegaly. The cohort continued to be well controlled and without changes in QoL. We measured a relatively favourable attitude towards the public health measures to prevent the spread of SARS-CoV2; in particular, patients who had a lower QoL had more positive attitudes towards these measures.

Detection and localization of hyperfunctioning parathyroid glands on [18F]fluorocholine PET/ CT using deep learning - model performance and comparison to human experts.

BACKGROUND: In the setting of primary hyperparathyroidism (PHPT), [18F]fluorocholine PET/CT (FCH-PET) has excellent diagnostic performance, with experienced practitioners achieving 97.7% accuracy in localising hyperfunctioning parathyroid tissue (HPTT). Due to the relative triviality of the task for human readers, we explored the performance of deep learning (DL) methods for HPTT detection and localisation on FCH-PET images in the setting of PHPT. PATIENTS AND METHODS: We used a dataset of 93 subjects with PHPT imaged using FCH-PET, of which 74 subjects had visible HPTT while 19 controls had no visible HPTT on FCH-PET. A conventional Resnet10 as well as a novel mPETResnet10 DL model were trained and tested to detect (present, not present) and localise (upper left, lower left, upper right or lower right) HPTT. Our mPETResnet10 architecture also contained a region-of-interest masking algorithm that we evaluated qualitatively in order to try to explain the model's decision process. RESULTS: The models detected the presence of HPTT with an accuracy of 83% and determined the quadrant of HPTT with an accuracy of 74%. The DL methods performed statistically worse (p < 0.001) in both tasks compared to human readers, who localise HPTT with the accuracy of 97.7%. The produced region-of-interest mask, while not showing a consistent added value in the qualitative evaluation of model's decision process, had correctly identified the foreground PET signal. CONCLUSIONS: Our experiment is the first reported use of DL analysis of FCH-PET in PHPT. We have shown that it is possible to utilize DL methods with FCH-PET to detect and localize HPTT. Given our small dataset of 93 subjects, results are nevertheless promising for further research.

Assessment of Eating Disorders and Eating Behavior to Improve Treatment Outcomes in Women with Polycystic Ovary Syndrome.

The essential role of the frequent coexistence of mental disorders and polycystic ovary syndrome (PCOS) is being increasingly recognized in the management of PCOS patients since it influences the success of weight loss interventions. Patients frequently experience disrupted eating behaviors, evidenced by the high prevalence of eating disorders in this population. Therefore, assessment and potential modification of eating disorders and eating-related behavior might be especially relevant to improve obesity treatment outcomes in this population, which remains the most efficient causal treatment in PCOS patients with high metabolic risk. Following a literature overview on common eating disorders and eating behaviors in PCOS, the aim of this review was to explore the prevalence and underlying mechanisms behind those occurrences. Understanding the clinical relevance of those associations and the addition of the assessments of eating disorders as well as eating phenotypes, eating chronotypes, and eating content as essential determinants of eating behavior could aid in the successful management of women with PCOS. In addition, the review also covers the potential of using eating disorders and eating behavior as a tool for the personalization of obesity treatment in PCOS.