Ketogenic Diet: A Nutritional Therapeutic Tool for Lipedema?

PURPOSE OF REVIEW: This review aims to provide an overview of the current evidence on the efficacy, also considering the anti-inflammatory properties and safety of very low-calorie ketogenic diet (VLCKD) as a potential treatment for lipedema, particularly in the context of obesity. RECENT FINDINGS: Lipedema is a chronic disease characterized by abnormal and painful fat buildup on the legs and/or arms. It is often misdiagnosed as obesity or lymphedema. However, although lipedema and obesity can coexist, unlike obesity, lipedema usually affects the legs and thighs without affecting the feet or hands, and the abnormal deposition of adipose tissue in lipedema is painful. The current lifestyle interventions are often unsuccessful in the management of lipedema. There is no consensus on the most effective nutritional approach for managing lipedema. Recent studies have suggested that VLCKD may be an effective treatment for lipedema, demonstrating that it is also superior to other nutritional approaches such as Mediterranean diet or intermittent fasting. Lipedema is a chronic and debilitating disease characterized by abnormal and painful accumulation of adipose tissue in the legs. VLCKD has been shown to be an effective treatment for lipedema, especially in the context of obesity, due to its anti-inflammatory properties. However, further research is needed to determine the long-term safety and efficacy of VLCKD as a treatment for lipedema.

"Time" for obesity-related cancer: The role of the circadian rhythm in cancer pathogenesis and treatment.

The circadian rhythm is regulated by an intrinsic time-tracking system, composed both of a central and a peripheral clock, which influences the cycles of activities and sleep of an individual over 24 h. At the molecular level, the circadian rhythm begins when two basic helix-loop-helix/Per-ARNT-SIM (bHLH-PAS) proteins, BMAL-1 and CLOCK, interact with each other to produce BMAL-1/CLOCK heterodimers in the cytoplasm. The BMAL-1/CLOCK target genes encode for the repressor components of the clock, cryptochrome (Cry1 and Cry2) and the Period proteins (Per1, Per2 and Per3). It has been recently demonstrated that the disruption of circadian rhythm is associated with an increased risk of developing obesity and obesity-related diseases. In addition, it has been demonstrated that the disruption of the circadian rhythm plays a key role in tumorigenesis. Further, an association between the circadian rhythm disruptions and an increased incidence and progression of several types of cancer (e.g., breast, prostate, colorectal and thyroid cancer) has been found. As the perturbation of circadian rhythm has adverse metabolic consequences (e.g., obesity) and at the same time tumor promoter functions, this manuscript has the aim to report how the aberrant circadian rhythms affect the development and prognosis of different types of obesity-related cancers (breast, prostate, colon rectal and thyroid cancer) focusing on both human studies and on molecular aspects.

Female infertility in the era of obesity: The clash of two pandemics or inevitable consequence?

Obesity is an epidemic that has led to a rise in the incidence of many comorbidities: among others, reduced fertility is often under-evaluated in clinical practice. The mechanisms underlying the link between reduced fertility and obesity are numerous, with insulin resistance, hyperglycaemia and the frequent coexistence of polycystic ovary syndrome being the most acknowledged. However, several other factors concur, such as gut microbiome alterations, low-grade chronic inflammation and oxidative stress. Not only do women with obesity take longer to conceive, but in vitro fertilization (IVF) is also less likely to succeed. We herein provide an updated state-of-the-art regarding the molecular bases of what we could define as dysmetabolic infertility, focusing on the clinical aspects, as well as possible treatment.

Age-dependent and sex-dependent disparity in mortality in patients with adrenal incidentalomas and autonomous cortisol secretion: an international, retrospective, cohort study.

BACKGROUND: The association between cortisol secretion and mortality in patients with adrenal incidentalomas is controversial. We aimed to assess all-cause mortality, prevalence of comorbidities, and occurrence of cardiovascular events in uniformly stratified patients with adrenal incidentalomas and cortisol autonomy (defined as non-suppressible serum cortisol on dexamethasone suppression testing). METHODS: We conducted an international, retrospective, cohort study (NAPACA Outcome) at 30 centres in 16 countries. Eligible patients were aged 18 years or older with an adrenal incidentaloma (diameter ≥1 cm) detected between Jan 1, 1996, and Dec 31, 2015, and availability of a 1 mg dexamethasone suppression test result from the time of the initial diagnosis. Patients with clinically apparent hormone excess, active malignancy, or follow-up of less than 36 months were excluded. Patients were stratified according to the 0800-0900 h serum cortisol values after an overnight 1 mg dexamethasone suppression test; less than 50 nmol/L was classed as non-functioning adenoma, 50-138 nmol/L as possible autonomous cortisol secretion, and greater than 138 nmol/L as autonomous cortisol secretion. The primary endpoint was all-cause mortality. Secondary endpoints were the prevalence of cardiometabolic comorbidities, cardiovascular events, and cause-specific mortality. The primary and secondary endpoints were assessed in all study participants. FINDINGS: Of 4374 potentially eligible patients, 3656 (2089 [57·1%] with non-functioning adenoma, 1320 [36·1%] with possible autonomous cortisol secretion, and 247 [6·8%] with autonomous cortisol secretion) were included in the study cohort for mortality analysis (2350 [64·3%] women and 1306 [35·7%] men; median age 61 years [IQR 53-68]; median follow-up 7·0 years [IQR 4·7-10·2]). During follow-up, 352 (9·6%) patients died. All-cause mortality (adjusted for age, sex, comorbidities, and previous cardiovascular events) was significantly increased in patients with possible autonomous cortisol secretion (HR 1·52, 95% CI 1·19-1·94) and autonomous cortisol secretion (1·77, 1·20-2·62) compared with patients with non-functioning adenoma. In women younger than 65 years, autonomous cortisol secretion was associated with higher all-cause mortality than non-functioning adenoma (HR 4·39, 95% CI 1·93-9·96), although this was not observed in men. Cardiometabolic comorbidities were significantly less frequent with non-functioning adenoma than with possible autonomous cortisol secretion and autonomous cortisol secretion (hypertension occurred in 1186 [58·6%] of 2024 patients with non-functioning adenoma, 944 [74·0%] of 1275 with possible autonomous cortisol secretion, and 179 [75·2%] of 238 with autonomous cortisol secretion; dyslipidaemia occurred in 724 [36·2%] of 1999 patients, 547 [43·8%] of 1250, and 123 [51·9%] of 237; and any diabetes occurred in 365 [18·2%] of 2002, 288 [23·0%] of 1250, and 62 [26·7%] of 232; all p values <0·001). INTERPRETATION: Cortisol autonomy is associated with increased all-cause mortality, particularly in women younger than 65 years. However, until results from randomised interventional trials are available, a conservative therapeutic approach seems to be justified in most patients with adrenal incidentaloma. FUNDING: Deutsche Forschungsgemeinschaft, Associazione Italiana per la Ricerca sul Cancro, Università di Torino.

Cardiometabolic Disease Burden and Steroid Excretion in Benign Adrenal Tumors : A Cross-Sectional Multicenter Study.

BACKGROUND: Benign adrenal tumors are commonly discovered on cross-sectional imaging. Mild autonomous cortisol secretion (MACS) is regularly diagnosed, but its effect on cardiometabolic disease in affected persons is ill defined. OBJECTIVE: To determine cardiometabolic disease burden and steroid excretion in persons with benign adrenal tumors with and without MACS. DESIGN: Cross-sectional study. SETTING: 14 endocrine secondary and tertiary care centers (recruitment from 2011 to 2016). PARTICIPANTS: 1305 prospectively recruited persons with benign adrenal tumors. MEASUREMENTS: Cortisol excess was defined by clinical assessment and the 1-mg overnight dexamethasone-suppression test (serum cortisol: <50 nmol/L, nonfunctioning adrenal tumor [NFAT]; 50 to 138 nmol/L, possible MACS [MACS-1]; >138 nmol/L and absence of typical clinical Cushing syndrome [CS] features, definitive MACS [MACS-2]). Net steroid production was assessed by multisteroid profiling of 24-hour urine by tandem mass spectrometry. RESULTS: Of the 1305 participants, 49.7% had NFAT (n = 649; 64.1% women), 34.6% had MACS-1 (n = 451; 67.2% women), 10.7% had MACS-2 (n = 140; 73.6% women), and 5.0% had CS (n = 65; 86.2% women). Prevalence and severity of hypertension were higher in MACS-2 and CS than NFAT (adjusted prevalence ratios [aPRs] for hypertension: MACS-2, 1.15 [95% CI, 1.04 to 1.27], and CS, 1.37 [CI, 1.16 to 1.62]; aPRs for use of ≥3 antihypertensives: MACS-2, 1.31 [CI, 1.02 to 1.68], and CS, 2.22 [CI, 1.62 to 3.05]). Type 2 diabetes was more prevalent in CS than NFAT (aPR, 1.62 [CI, 1.08 to 2.42]) and more likely to require insulin therapy for MACS-2 (aPR, 1.89 [CI, 1.01 to 3.52]) and CS (aPR, 3.06 [CI, 1.60 to 5.85]). Urinary multisteroid profiling revealed an increase in glucocorticoid excretion from NFAT over MACS-1 and MACS-2 to CS, whereas androgen excretion decreased. LIMITATIONS: Cross-sectional design; possible selection bias. CONCLUSION: A cardiometabolic risk condition, MACS predominantly affects women and warrants regular assessment for hypertension and type 2 diabetes. PRIMARY FUNDING SOURCE: Diabetes UK, the European Commission, U.K. Medical Research Council, the U.K. Academy of Medical Sciences, the Wellcome Trust, the U.K. National Institute for Health Research, the U.S. National Institutes of Health, the Claire Khan Trust Fund at University Hospitals Birmingham Charities, and the Mayo Clinic Foundation for Medical Education and Research.

Obstructive Sleep Apnea Is Associated With Low Testosterone Levels in Severely Obese Men.

Background: Disrupted sleep affects cardio-metabolic and reproductive health. Obstructive sleep apnea syndrome represents a major complication of obesity and has been associated with gonadal axis activity changes and lower serum testosterone concentration in men. However, there is no consistent opinion on the effect of obstructive sleep apnea on testosterone levels in men. Objective: The aim of this study was to determine the influence of obstructive sleep apnea on total and free testosterone levels in severely obese men. Materials and methods: The study included 104 severely obese (Body Mass Index (BMI) ≥ 35 kg/m2) men, aged 20 to 60, who underwent anthropometric, blood pressure, fasting plasma glucose, lipid profile, and sex hormone measurements. All participants were subjected to polysomnography. According to apnea-hypopnea index (AHI) patients were divided into 3 groups: <15 (n = 20), 15 - 29.9 (n = 17) and ≥ 30 (n = 67). Results: There was a significant difference between AHI groups in age (29.1 ± 7.2, 43.2 ± 13.2, 45.2 ± 10.2 years; p < 0.001), BMI (42.8 ± 5.9, 43.2 ± 5.9, 47.1 ± 7.8 kg/m2; p = 0.023), the prevalence of metabolic syndrome (MetS) (55%, 82.4%, 83.6%, p = 0.017), continuous metabolic syndrome score (siMS) (4.01 ± 1.21, 3.42 ± 0.80, 3.94 ± 1.81, 4.20 ± 1.07; p = 0.038), total testosterone (TT) (16.6 ± 6.1, 15.2 ± 5.3, 11.3 ± 4.44 nmol/l; p < 0.001) and free testosterone (FT) levels (440.4 ± 160.8, 389.6 ± 162.5, 294.5 ± 107.0 pmol/l; p < 0.001). TT level was in a significant negative correlation with AHI, oxygen desaturation index (ODI), BMI, MetS and siMS. Also, FT was in a significant negative correlation with AHI, ODI, BMI, age, MetS and siMS. The multiple regression analysis revealed that both AHI and ODI were in significant correlation with TT and FT after adjustment for age, BMI, siMS score and MetS components. Conclusion: Obstructive sleep apnea is associated with low TT and FT levels in severely obese men.

Approach to the Patient with Subclinical Cushing's Syndrome.

A growing number of patients with adrenal incidentalomas and subclinical Cushing's syndrome (SCS) led to an increasing number of different guidelines, and diagnostic and treatment recommendations. Excess cortisol secretion in patients with SCS is associated with several comorbidities, such as hypertension, dyslipidemia, type 2 diabetes mellitus, and obesity, which in the long-term increase mortality of these patients. Subtle cortisol secretion affects bone health, quality of life and causes depression, but due to the unapparent clinical features, patients with SCS are often at risk between over and under treatment. This narrative review aimed to summarize the latest recommendations on the approach to the patient with subclinical Cushing's syndrome.

Menopausal hyperinsulinism and hypertension - new approach.

Aim: to test effects of estradiol (E2) 1 mg and drospirenone (DRSP) 2 mg in treatment of normal weight menopausal women with typical menopausal symptoms, hyperinsulinism, and grade I hypertension.Material and methods: The participants were 133 menopausal women, mean age 51.82 ± 3.25 years, body mass index (BMI) 24.9 ± 2.6 kg/m2, waist/hip 0.80 ± 0.05, amenorrhoeic period 2.12 ± 2.10 years. All patients were treated with E2 1 mg and DRSP 2 mg during 12 months period. Blood samples were taken at 8 am before and during 12 months of therapy for: glycemia, lipids, hormonal analysis, follicle-stimulating hormone (FSH), luteinizing hormone (LH), E2, testosterone (T), prolactin (PRL), dehydroepiandrosterone sulfate (DHEAS), and sex hormone-binding globulin (SHBG). Oral glucose tolerance test (OGTT) was performed with 75 g glucose in order to assess insulin secretion. All had grade I hypertension 24 h blood pressure monitoring was performed before and after 12 months of therapy.Results: E2/DRSP significantly decreased total cholesterol, low-density lipoprotein (LDL), apolipoprotein B (ApoB), and increased high-density lipoprotein cholesterol (HDL) and apolipoprotein A (ApoA). Insulin area under the curve (AUC) significantly decreased (6586.1 ± 4194.2 vs. 5315.3 ± 2895.0, p < .05) and homeostatic model assessment (HOMA) (3.53 ± 2.18 vs. 3.0 ± 1.8, p < .05). FSH, LH decreased, E2 increased significantly. Of 24 h day blood pressure decreased significantly.Conclusions: E2/DRSP represents suitable therapy for hyperinsulinemic, grade I hypertensive menopausal women with typical symptoms and normal weight.

Therapeutic strategies for type 2 diabetes mellitus in women after menopause.

As type 2 diabetes mellitus (T2DM) is affected by both chronological and ovarian ageing, it is common in postmenopausal women. This review analyses and critically appraises the literature regarding the optimal therapeutic strategies for T2DM in women after menopause. Lifestyle interventions, including changes in dietary habits and physical exercise in everyday life targeting a modest weight loss (5%), represent the cornerstone of management. Limited intake of alcohol and sodium, as well as smoking cessation, are additional lifestyle changes for both endothelial and bone health. Regarding medications, postmenopausal women should be initially treated with metformin, concurrently with lifestyle intervention. If glycosylated haemoglobin (HbA1c) remains over the target level (usually ≥7%), dipeptidyl peptidase-4 inhibitors (DPP-4i) or glucagon-like peptide-1 receptor agonists (GLP-1RA) should be preferred. Thiazolidinediones (TZDs) and canagliflozin should be avoided in postmenopausal women with increased fracture risk. Insulin should be used with caution to avoid hypoglycaemia. Bariatric surgery is a well established and effective therapeutic option for both weight loss and glycaemic control in very obese patients with T2DM; however, metabolic benefits should be balanced against nutritional deficiencies that often present after surgery. Proper control of hypertension, with avoidance of hypotension, is of great importance as a measure against falls. Annual tests for retinopathy and neuropathy are crucial for the same reason. Menopausal hormone therapy (MHT) has a beneficial effect on glucose homeostasis, reduces the risk of new-onset T2DM and improves glucose control in women with T2DM. T2DM has been considered a cardiovascular disease equivalent, which meant that postmenopausal women with the disease could not take MHT but current evidence supports an individualised approach to this issue. Therapeutic strategies for women with T2DM after menopause should aim to maximise benefits for metabolic, cardiovascular and bone health with the minimum of adverse effects, bearing in mind that most women will spend more than one-third of their life being of postmenopausal status.

Luteinizing hormone and insulin resistance in menopausal patients with adrenal incidentalomas: The cause-effect relationship?

OBJECTIVE: A high prevalence of insulin resistance (IR) has proven to manifest in patients with adrenal incidentalomas (AI). It has been demonstrated that an increase in IR is related to the size of tumourous masses; additionally, luteinizing hormone (LH)-dependent adrenal pathologies are well documented in patients with LH-responsive adrenal tumours occurring under conditions of physiologically elevated LH. We hypothesized that an association between LH and insulin might play a role in adrenal tumourigenesis and steroidogenesis. DESIGN: The aim of our study was to investigate the association between LH and IR; adrenal tumour size (ATS) and IR; LH and cortisol after the 1 mg overnight dexamethasone test (1 mg DST); and ATS and 1 mg DST cortisol in AI patients. This was a case-control study conducted in the Clinic for Endocrinology, Diabetes and Metabolic Diseases in Belgrade, Serbia. The total study group consisted of 105 menopausal women: 75 AI patients [27 with nonfunctional AI (NAI) and 48 with (possible) autonomous cortisol secretion ((P)ACS)] and 30 age-, BMI-, LH- and menopause duration-matched healthy control (HC) women. To estimate IR, we used homeostasis model assessment (HOMA-IR). RESULTS: Luteinizing hormone and ATS are in a significant positive correlation with HOMA-IR and 1 mg DST cortisol in menopausal patients with AI and (P)ACS. CONCLUSIONS: Our data point to a possible cause-effect relationship between LH and insulin in patients with AI and (P)ACS adding to the body of evidence of their involvement in adrenal tumourigenesis and steroidogenesis.

Acquired Hypertrichosis Lanuginosa: Typical Presentation and Unusual Association.

Paraneoplastic syndrome might be the first clinical manifestation of malignancy. We present a menopausal female with the acquired hypertrichosis lanuginosa (AHL) as an initial clinical presentation of rectal adenocarcinoma, unusually associated with paraneoplastic cerebellar degeneration (PCD) and disseminated intravascular coagulation (DIC).

[Complete androgen insensitivity syndrome].

SUMMARY INTRODUCTION: Androgen insensitivity syndrome (AIS) belongs to disorders of sex development, resulting from complete or partial resistance to the biological actions of androgens in persons who are genetically males (XY) with normally developed testes and age-appropriate for males of serum testosterone concentration. CASE OUTLINE: A 21-year-old female patient was admitted at our Clinic further evaluation and treatment of testicular feminization syndrome, which was diagnosed at the age of 16 years.The patient had never menstruated. On physical examination, her external genitalia and breast development appeared as completely normal feminine structures but pubic and axillary hair was absent. Cytogenetic analysis showed a 46 XY karyotype. The values of sex hormones were as in adult males. The multi-sliced computed tomography (MSCT) showed structures on both sides of the pelvic region, suggestive of testes. Bilateral orchiectomy was performed. Hormone replacement therapy was prescribed after gonadectomy. Vaginal dilatation was advised to avoid dyspareunia. CONCLUSION: The diagnosis of complete androgen insensitivity is based on clinical findigs, hormonal analysis karyotype, visualization methods and genetic analysis. Bilateral gonadectomy is generally recommended in early adulthood to avoid the risk of testicular malignancy. Vaginal length may be short requiring dilatation in an effort to avoid dyspareunia. Vaginal surgery is rarely indicated for the creation of a functional vagina.

Finger length ratios in Serbian transsexuals.

Atypical prenatal hormone exposure could be a factor in the development of transsexualism. There is evidence that the 2nd and 4th digit ratio (2D:4D) associates negatively with prenatal testosterone and positively with estrogens. The aim was to assess the difference in 2D:4D between female to male transsexuals (FMT) and male to female transsexuals (MFT) and controls. We examined 42 MFT, 38 FMT, and 45 control males and 48 control females. Precise measurements were made by X-rays at the ventral surface of both hands from the basal crease of the digit to the tip using vernier calliper. Control male and female patients had larger 2D:4D of the right hand when compared to the left hand. Control male's left hand ratio was lower than in control female's left hand. There was no difference in 2D:4D between MFT and control males. MFT showed similar 2D:4D of the right hand with control women indicating possible influencing factor in embryogenesis and consequently finger length changes. FMT showed the lowest 2D:4D of the left hand when compared to the control males and females. Results of our study go in favour of the biological aetiology of transsexualism.

Nondiabetic patients with either subclinical Cushing's or nonfunctional adrenal incidentalomas have lower insulin sensitivity than healthy controls: clinical implications.

OBJECTIVE: The aim of this study was to estimate insulin sensitivity (IS) in nondiabetic patients with adrenal incidentalomas (AI): nonfunctional adrenal incidentalomas (NAI) and patients with AI and subclinical Cushing's syndrome (SCS). METHODS: Based on the inclusion criteria (normal fasting glucose levels, no previous history of impaired fasting glucose and/or diabetes, and no medications or concomitant relevant diseases) and the exclusion criteria (pheochromocytoma, overt hypercortisolism, hyperaldosteronism, adrenal carcinoma, metastasis of extra-adrenal tumors, extra-adrenal malignancies), 142 subjects were drawn from a series of patients with AI. The subjects were age-, sex- and body mass index (BMI)-matched: 70 with NAI (50 women and 20 men), 37 with AI and SCS (31 women and 6 men) and 35 healthy control (HC) subjects (30 women and 5 men). The oral glucose tolerance test (OGTT) and several indices of insulin sensitivity (IS) were used: homeostasis model assessment (HOMA), quantitative insulin sensitivity check index (QUICKI), triglycerides and glucose index (TyG), index of whole-body insulin sensitivity (ISI-composite) and glucose to insulin ratio (G/I). RESULTS: There was a significant difference in IS between subjects with NAI and HC (HOMA, p=0.049; QUICKI, p=0.036; TyG, p=0.002; ISI-composite, p=0.024) and subjects with SCS and HC (AUC insulin, p=0.01; HOMA, p=0.003; QUICKI, p=0.042; TyG, p=0.008; ISI-composite, p=0.002). There was no difference in the tested indices of IS between subjects with NAI and SCS (p>0.05). However, subjects with SCS had a significantly higher prevalence of impaired glucose tolerance and higher area under the curve for glucose than subjects with NAI (p=0.0174). The linear regression analysis showed that 1 mg-DST cannot be used as a predictor of HOMA (R(2)=0.004, F=0.407, p=0.525). Significant relationship was found between 1 mg-DST and ISI-composite (R(2)=0.042, F=4.981, p=0.028) but this relationship was weak and standard error of estimate was high. The linear regression model also showed that ACTH cannot be used as a predictor of HOMA (R(2)=0.001, F=0.005, p=0.943) or ISI-composite (R(2)=0.015, F=1.819, p=0.187). CONCLUSIONS: Insulin resistance is a major cardiovascular risk factor; therefore, the assessment of IS in patients with AI, even nonfunctional, has a valuable place in the endocrine workup of these patients.

Decreased glutathione levels and altered antioxidant defense in an animal model of schizophrenia: long-term effects of perinatal phencyclidine administration.

Perinatal phencyclidine (PCP) administration to rodents represents one of the more compelling animal models of schizophrenia. There is evidence that decreased glutathione (GSH) levels and oxidative stress mediated through free radicals in the central nervous system are involved in the pathophysiology of this disease. Limited data are available on the role of free radicals in neurotoxicity induced by NMDA-receptor antagonists. The aim of this study was to elucidate the long-term effects of perinatal phencyclidine administration on superoxide dismutase (SOD), catalase (CAT), gamma-glutamyl cisteine ligase (gamma-GCL), glutathione peroxidase (GPx), glutathione reductase (GR) and levels of lipid peroxides as well as GSH content. The Wistar rats were treated on the 2nd, 6th, 9th and 12th postnatal (PN) days with either phencyclidine (10mg/kg) or saline and sacrificed on PN70. The activities of antioxidant enzymes and level of lipid peroxides and GSH were determined in dorsolateral frontal cortex (dlFC), hippocampus, thalamus and caudate nucleus. Expression of SOD1 and SOD2 was determined by immunoblot. Region-specific changes of the measured parameters were observed. Decreased content of reduced GSH and altered activities of GR, GPx and SOD were determined in dlFC. In hippocampus, reduced GSH content and decreased activities of GPx and GR were accompanied with increased activity of gamma-GCL and increased level of lipid peroxides. gamma-GCL and GSH content were also decreased in caudate nucleus, while in thalamus major findings are increased levels of lipid peroxides and GR activity and decreased gamma-GCL activity. It can be concluded that perinatal PCP administration produces long-term alteration of antioxidant defense. Further studies are necessary in order to clarify role of redox dysregulation in the pathogenetic mechanism of schizophrenia.