Characterisation of the urinary steroid profile of patients with nonfunctioning adrenal incidentalomas: A matched controlled cross-sectional study.

AIM: To identify alterations in steroid metabolism in patients with nonfunctioning adrenal incidentalomas (NFAIs) through the analysis of their urinary steroid profile (USP). METHODS: Cross-sectional study with one study group (NFAIs, cortisol post dexamethasone suppression test [DST] ≤ 1.8 µg/dl [49.7 nmol/L]) and 2 control groups: patients with autonomous cortisol secretion (ACS group, cortisol post-DST > 1.8 µg/dl (49.7 nmol/L) and patients without adrenal tumours (healthy-adrenal group). Twenty-four-hour urine collections for USP measurement (total and free fraction of 51 24 h-urine specimens) were obtained from 73 participants (24 with NFAIs, 24 without AIs, and 25 with ACS). USP was determined by gas chromatography coupled to mass spectrometry. Patients of the three groups were matched according to sex, age (±5 years-old) and body mass index (±5 kg/m2 ). RESULTS: Compared to healthy-adrenal controls, patients with NFAIs had a lower excretion of androgen metabolites (230.5 ± 190.12 vs. 388.7 ± 328.58 µg/24 h, p = .046) and a higher excretion of urinary free cortisol (UFC) (54.3 ± 66.07 vs. 25.4 ± 11.16 µg/24 h, p = .038). UFC was above the reference range in 20.8% of patients in the NFAI, compared to 0% in the healthy-adrenal group (p = .018). Patients with ACS had a higher prevalence of hypertension, dyslipidemia, and diabetes than patients with NFAIs or the control group. A lower excretion of androgen metabolites (218.4 ± 204.24 vs. 231 ± 190 µg/24 h, p = .041) and a nonsignificant higher excretion of glucocorticoid metabolites (2129.6 ± 1195.96 vs. 1550.8 ± 810.03 µg/24 h, p = .180) was found in patients with ACS compared to patients with NFAIs. CONCLUSION: NFAIs seem to secrete a subtle, yet clinically relevant, excess of glucocorticoids. Future studies are needed to confirm our findings; and to identify metabolic alterations associated with an increased cardiometabolic risk.

Sex differences and sex steroids influence on the presentation and severity of cardiovascular autonomic neuropathy of patients with type 1 diabetes.

BACKGROUND: Sex differences characterize cardiovascular outcomes in patients with type 1 diabetes. Cardioautonomic neuropathy is a common complication of type 1 diabetes that associates increased morbi-mortality. Data regarding the interplay between sex and cardiovascular autonomic neuropathy are scarce and controversial in these patients. We aimed to address sex-related differences in the prevalence of seemingly asymptomatic cardioautonomic neuropathy in type 1 diabetes, and their associations with sex steroids. METHODS: We conducted a cross-sectional study including 322 consecutively recruited patients with type 1 diabetes. Cardioautonomic neuropathy was diagnosed using Ewing's score and power spectral heart rate data. We assessed sex hormones by liquid chromatography/tandem mass spectrometry. RESULTS: When considering all subjects as a whole, asymptomatic cardioautonomic neuropathy prevalence was not significantly different between women and men. When age was taken into account, the prevalence of cardioautonomic neuropathy was similar among young men and those > 50 years. However, in women > 50 years, the prevalence of cardioautonomic neuropathy doubled that of young women [45.8% (32.6; 59.7) vs. 20.4% (13.7; 29.2), respectively]. The OR of having cardioautonomic neuropathy was 3.3 higher in women > 50 years than in their younger counterparts. Furthermore, women presented more severe cardioautonomic neuropathy than men. These differences were even more marked when women were classified according their menopausal status instead of age. Peri- and menopausal women had an OR 3.5 (1.7; 7.2) of having CAN compared with their reproductive-aged counterparts [CAN prevalence: 51% (37; 65) vs. 23% (16; 32), respectively]. A binary logistic regression model (R2: 0.161; P = 0.001) displayed age > 50 years as a significant determinant of cardioautonomic neuropathy only in women. Androgens were positively associated with heart rate variability in men, and negatively in women. Accordingly, cardioautonomic neuropathy was associated with increased testosterone/estradiol ratio in women but to decreased testosterone concentrations in men. CONCLUSIONS: Menopause in women with type 1 diabetes is accompanied by an increase in the prevalence of asymptomatic cardioautonomic neuropathy. This age-related excess risk of cardioautonomic neuropathy is not observed in men. Men and women with type 1 diabetes have opposite associations between circulating androgens and indexes of cardioautonomic function. Trial registration ClinicalTrials.gov Identifier: NCT04950634.

Evaluation of Body Composition in Patients With and Without Adrenal Tumors and Without Overt Hypersecretory Syndromes.

OBJECTIVE: To compare body composition between patients with autonomous cortisol secretion (ACS), those with nonfunctioning adrenal incidentalomas (NFAIs), and control subjects without adrenal tumors. METHODS: A cross-sectional study was performed, incluidng the following 3 groups: patients with ACS (cortisol post-dexamethasone suppression test [DST] >1.8 µg/dL), NFAIs (cortisol post-DST ≤ 1.8 µg/dL), and patients without adrenal tumors (control group). Patients of the 3 groups were matched according to age (±5 years), sex, and body mass index (±5 kg/m2). Body composition was evaluated by bioelectrical impedance and abdominal computed tomography (CT) and urinary steroid profile by gas chromatography mass spectrometry. RESULTS: This study enrolled 25 patients with ACS, 24 with NFAIs, and 24 control subjects. Based on CT images, a weak positive correlation between the serum cortisol level post-DST and subcutaneous fat area (r = 0.3, P =.048) was found. As assessed by bioelectrical impedance, lean mass and bone mass were positively correlated with the excretion of total androgens (r = 0.56, P <.001; and r = 0.58, P <.001, respectively); visceral mass was positively correlated with the excretion of glucocorticoid metabolites and total glucocorticoids (r = 0.28, P =.031; and r = 0.42, P =.001, respectively). Based on CT imaging evaluation, a positive correlation was observed between lean mass and androgen metabolites (r = 0.30, P =.036) and between visceral fat area, total fat area, and visceral/total fat area ratio and the excretion of glucocorticoid metabolites (r = 0.34, P =.014; r = 0.29, P =.042; and r = 0.31, P =.170, respectively). CONCLUSION: The urinary steroid profile observed in adrenal tumors, comprising a low excretion of androgen metabolites and high excretion of glucocorticoid metabolites, is associated with a lower lean mass and bone mass and higher level of visceral mass in patients with adrenal tumors.

Glycoprotein A and B Height-to-Width Ratios as Obesity-Independent Novel Biomarkers of Low-Grade Chronic Inflammation in Women with Polycystic Ovary Syndrome (PCOS).

The polycystic ovary syndrome (PCOS) is a common endocrine disorder affecting women in reproductive age. Obesity and low-grade chronic inflammation are frequently associated with PCOS. Recently, proton nuclear magnetic resonance (1H-NMR)-derived glycoprotein profiles have emerged as potential biomarkers that reflect systemic inflammation in type 2 diabetes, obesity, and other pathological processes. The aim of this work is to study plasma glycoprotein profiles as metabolic/inflammatory biomarkers underlying PCOS and its association with inflammation and obesity. We used 1H-NMR spectroscopy to study five glycoprotein variables, namely GlycA, GlycB, and GlycF and the height-to-width (H/W) ratio of GlycA and GlycB, in 17 women with PCOS (9 non-obese and 8 obese), 17 control women (9 non-obese and 8 obese), and 19 healthy men (10 non-obese and 9 obese). H/W ratios of GlycA and GlycB, but not glycoprotein areas, were specifically associated with PCOS independently of obesity. When considered as a whole, obese subjects presented higher GlycA, GlycB, and GlycF areas and higher H/W GlycA and GlycB ratios than their non-obese counterparts. All glycoprotein variables were associated with hsCRP, IL-6, and TNF-α, showing different correlations among PCOS, women, and men. Our present exploratory results suggest that 1H-NMR-derived glycoprotein profiles might serve as novel diagnostic markers of low-grade chronic inflammation in women with PCOS.

The peripheral atherosclerotic profile in patients with type 1 diabetes warrants a thorough vascular assessment of asymptomatic patients.

AIMS: Epidemiological data on subclinical atherosclerotic disease in type 1 diabetes mellitus (DM1) are scarce. We aimed to estimate the subclinical atherosclerosis profile of asymptomatic patients with DM1 and an abnormal ankle-brachial index (ABI). MATERIAL AND METHODS: In a cross-sectional design (ClinicalTrials.gov Identifier: NCT02910271), we estimated ABI in 289 consecutive asymptomatic patients with DM1. An abnormal ABI led to measurements of toe-brachial index (TBI) and peripheral doppler ultrasound (DUS) to diagnose peripheral artery disease (PAD) and/or atherosclerotic carotid plaques (ACP). RESULTS: A reduced (≤0.9) or increased (>1.2) ABI was detected in 17 (6%) and 75 (26%) patients, respectively. PAD was confirmed by TBI and DUS in 9 (53%) patients with a reduced ABI and 28 (37%) patients with an increased ABI, resulting in a 12.8% (9.4-17.2) prevalence of asymptomatic PAD. Fourteen patients with an abnormal ABI also exhibited ACP [4.8% (2.9-7.9)], with 64% of these patients showing bilateral disease. Artery stenosis was mild or moderate in 21% and 29% of patients, respectively. Thus, 46 [16% (12-21)] patients showed asymptomatic PAD, ACP, or both. According to our data, we would have to explore three asymptomatic patients with DM1 and normal pulses to unmask one case of PAD, and seven asymptomatic patients showing abnormal ABI values to detect one carotid disease. CONCLUSIONS: Peripheral artery disease is often undiagnosed in asymptomatic patients with DM1. However, its presence may change medical management in a substantial percentage of cases, highlighting the potential benefit of a thorough vascular assessment on these patients.

Certified testosterone immunoassays for hyperandrogenaemia.

BACKGROUND: Testosterone (T) measurement in women is problematic leading to initiatives aiming to improve laboratory standardization of commercial assays. We assessed the impact on the clinical diagnosis of functional hyperandrogenic disorders of a total T immunoassay recently certified by the Centers for Diseases Control and Prevention (CDC). METHODS: We conducted a cross-sectional study including 263 consecutive adult premenopausal women presenting with functional ovarian hyperandrogenism-including polycystic ovary syndrome (PCOS)-and 73 nonhyperandrogenic female volunteers who served to define reference ranges. Total T was measured by a local routine direct radioimmunoassay and by a CDC-certified immunochemiluminescence assay. The main outcome measures were total and calculated free T concentrations and percentage of patients with hyperandrogenaemia. RESULTS: Both assays showed a poor concordance for total and calculated free T measurements. Hence, 147 (56%) and 109 (41%) of women had hyperandrogenaemia with the routine and CDC-certified assays, respectively [κ (95%CI): 0.538 (0.441-0.634)]. Free T levels calculated from total T using both assays showed similar correlations with metabolic variables. Women showing hyperandrogenaemia by both methods had the worst metabolic profiles, yet women presenting with hyperandrogenaemia only when using the CDC-certified assay did not show any significant difference compared to nonhyperandrogenic women in anthropometric or metabolic variables. Those women with hyperandrogenaemia only when using the routine assay were more obese and insulin resistant than normoandrogenaemic hirsute patients. CONCLUSIONS: An isolated androgen measurement, even a very specific one, is unlikely to identify the hyperandrogenic milieu that characterizes patients with functional ovarian hyperandrogenism and PCOS.

Serum Retinol, Folic Acid, and Copper Are Associated With Sperm Abnormalities in Men With Obesity.

BACKGROUND AND OBJECTIVES: Micronutrients may influence the development and differentiation of sperm cells. The aim of this study was to assess the possible association of deficiencies in several vitamins and trace elements with sperm abnormalities in men with obesity. PARTICIPANTS AND METHODS: Thirty male patients with moderate to severe obesity and ten lean controls who gave written informed consent were included. Anthropometric parameters were recorded. Hormonal and lipid profiles were analyzed, as well as serum concentrations of zinc, copper, retinol, α-tocopherol, 25-hydroxyvitamin D, cobalamin, and folic acid. For sperm analysis, we used the reference values proposed by the World Health Organization. RESULTS: Fourteen of the thirty men (47%) presented abnormal sperm results. The most common abnormality was low motility in 33% of them, followed by low sperm concentration in 27% of the patients. Patients with abnormal sperm results showed lower serum folic acid (p = 0.005) and higher serum estradiol (p = 0.015) and copper (p = 0.033) than lean controls. The ejaculate volume inversely correlated with body mass index (BMI; r = -0.378, p = 0.016) and serum estradiol (r = -0.328, p = 0.041). Total number of sperm correlated inversely with BMI (r = -0.428, p = 0.006) and serum estradiol (r = -0.507, p = 0.001) and positively with serum folic acid (r = 0.356, p = 0.026) and retinol (r = 0.421, p = 0.009). Total motility of sperm inversely correlated with BMI (r = -0.433, p = 0.005), serum estradiol (r = -0.475, p = 0.002), and copper (r = -0.416, p = 0.012) and positively correlated with serum folic acid (r = 0.522, p = 0.001) and retinol (r = 0.350, p = 0.034). CONCLUSIONS: Sperm abnormalities in men with obesity are associated with excess body weight and micronutrient concentrations.

The Role of Androgen Excess in Metabolic Dysfunction in Women : Androgen Excess and Female Metabolic Dysfunction.

Polycystic ovary syndrome (PCOS) is characterized by the association of androgen excess with chronic oligoovulation and/or polycystic ovarian morphology, yet metabolic disorders and classic and nonclassic cardiovascular risk factors cluster in these women from very early in life. This chapter focuses on the mechanisms underlying the association of PCOS with metabolic dysfunction, focusing on the role of androgen excess on the development of visceral adiposity and adipose tissue dysfunction.

The role of serum osteoprotegerin and receptor-activator of nuclear factor-κB ligand in metabolic bone disease of women after obesity surgery.

Metabolic bone disease may appear as a complication of obesity surgery. Because an imbalance in the osteoprotegerin and receptor-activator of nuclear factor-κB ligand system may underlie osteoporosis, we aimed to study this system in humans in the metabolic bone disease occurring after obesity surgery. In this study we included sixty women with a mean age of 47 ± 10 years studied 7 ± 2 years after bariatric surgery. The variables studied were bone mineral density, ß-isomer of C-terminal telopeptide of type I collagen cross-links (a bone resorption marker), the bone formation markers osteocalcin and N-terminal propeptide of procollagen 1, serum osteoprotegerin and receptor-activator of nuclear factor-κB ligand. Serum osteoprotegerin inversely correlated with the bone remodeling markers osteocalcin, ß-isomer of C-terminal telopeptide of type I collagen cross-links and N-terminal propeptide of procollagen 1. The osteoprotegerin and receptor-activator of nuclear factor-κB ligand ratio also correlated inversely with serum parathormone and osteocalcin. Bone mineral density at the lumbar spine was associated with age (ß = -0.235, P = 0.046), percentage of weight loss (ß = 0.421, P = 0.001) and osteoprotegerin and receptor-activator of nuclear factor-κB ligand ratio (ß = 0.259, P = 0.029) in stepwise multivariate analysis (R 2 = 0.29, F = 7.49, P < 0.001). Bone mineral density at the hip site was associated only with percentage of weight loss (ß = 0.464, P < 0.001) in stepwise multivariate regression (R 2 = 0.21, F = 15.1, P < 0.001). These data show that the osteoprotegerin and receptor-activator of nuclear factor-κB ligand system is associated with bone markers and bone mineral density at the lumbar spine after obesity surgery.

Proteomic analysis of adipose tissue: informing diabetes research.

Diabetes, one of the most common endocrine diseases worldwide, results from complex pathophysiological mechanisms that are not fully understood. Adipose tissue is considered a major endocrine organ and plays a central role in the development of diabetes. The identification of the adipose tissue-derived factors that contribute to the onset and progression of diabetes will hopefully lead to the development of preventive and therapeutic interventions. Proteomic techniques may be useful tools for this purpose. In the present review, we have summarized the studies conducting adipose tissue proteomics in subjects with diabetes and insulin resistance, and discussed the proteins identified in these studies as candidates to exert important roles in these disorders.

The striking similarities in the metabolic associations of female androgen excess and male androgen deficiency.

Androgen excess in women and androgen deficiency in men facilitate abdominal adiposity and related metabolic disorders. Moreover, obesity-associated gonadal dysfunction consists of hyperandrogenism in women but hypogonadism in men. We have reviewed the existing evidence on the interplay between sex steroids, adipose tissue and lean mass distribution, and developed a novel hypothesis to explain these apparent paradoxes. We hypothesize that the most beneficial adipose tissue distribution and function is that of normal women, who have low androgen and high estrogen concentrations. Any imbalance favoring an increase in androgen levels in women, and the very high androgen levels characteristic of healthy men, influence adipose tissue distribution and function. Sex steroids determine a favorable (female) or unfavorable (male) body fat distribution and function. However, sex hormones also provide defensive mechanisms against visceral fat accumulation: androgens increase lean and muscle mass in men, decreasing the amount of visceral fat relative to total body mass and its negative consequences, whereas estrogens determine the metabolically safer deposition of body fat into the subcutaneous gluteal-femoral depot in women. This delicate equilibrium may be altered by the presence of gonadal dysfunction, a sedentary life-style or the normal ageing process leading to sarcopenia, and by the development of obesity leading to abdominal adiposity and metabolic disorders in both sexes. In conclusion, sex hormones and gonadal dysfunction play important roles in the pathogenesis of diabesity and its metabolic associations.

Polycystic ovary syndrome as a paradigm for prehypertension, prediabetes, and preobesity.

The polycystic ovary syndrome (PCOS) is a hyperandrogenic disorder affecting 5-10 % of premenopausal women. These patients gather multiple cardiovascular risk factors from early ages. Hence, PCOS is currently considered a paradigm of cardiometabolic disease. Research about its pathogenesis has grown over the last years, covering from the potential fetal developmental programming to the molecular basis of adipose tissue dysfunction, insulin resistance, inflammation, oxidative stress, sympathetic hyperactivity, and endothelial dysfunction. All these abnormalities put these patients at an increased risk of vascular events. Thus, practitioners attending these women must have a broad pathophysiological knowledge of PCOS. We here review recent scientific insights about its cardiometabolic phenotype focusing on the pathogenesis of obesity, type 2 diabetes mellitus, and hypertension. We emphasize that a diagnosis of PCOS, especially if accompanied by excess weight, must be followed by a complete and periodical cardiometabolic evaluation and by the aggressive management of the abnormalities identified, with the aim of preventing future cardiovascular morbidity.

Proteomics and polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is a complex endocrine disorder of heterogeneous etiology. Proteomics techniques have been used for elucidating the physiopathology of PCOS, yet the proteins identified so far were rarely the same across tissues and studies. The present review discusses the current challenges in the application of proteomics to the study of PCOS. A well-defined research design and an appropriate selection of study populations, samples and proteomic platforms are essential in clinical proteomics. Furthermore, the findings derived from proteomic approaches should be validated by complementary techniques, and the reproducibility of the results has ideally to be confirmed by different studies. Only when meeting these requirements, the proteins identified by proteomic techniques should be considered as candidates for future studies aiming to define specific molecular phenotypes of PCOS and their possible role in the metabolic and hormonal abnormalities characteristic of this syndrome.

Prevalence of hyperprolactinaemia in female premenopausal blood donors.

OBJECTIVE: The prevalence of asymptomatic hyperprolactinaemia has been widely studied in certain populations such as antipsychotic drugs users, infertile women or patients with primary hypothyroidism, but data on the prevalence of hyperprolactinaemia and macroprolactinaemia in the healthy population are very scarce in the literature. We aimed to obtain an unbiased estimation of the prevalence in premenopausal women of: (i) hyperprolactinaemia and (ii) its aetiology, including macroprolactinaemia and stress-related hyperprolactinaemia, while considering simultaneously the use of hormonal contraceptives. DESIGN: Prevalence survey. SUBJECTS: Three-hundred and ninety-three consecutive premenopausal women reporting spontaneously for blood donation. MEASUREMENTS: We performed an exhaustive clinical history and physical examination, establishing the presence of hirsutism, acne, alopecia, menstrual dysfunction and reproductive history. We also measured serum prolactin (PRL) (ruling out macroprolactinaemia when indicated), thyrotrophin, total testosterone, androstendione, sex hormone binding globulin and dehydroepiandrosterone sulphate concentrations. RESULTS: Serum PRL concentrations were increased in 16 of 393 women (4·1% prevalence, 95% CI: 2·1-6·0). The prevalence of macroprolactinaemia was 0·6% (95% CI: 0-1) in the total female blood donor population and was 12·5% (95% CI: 6-31) among hyperprolactinaemic patients. The remaining hyperprolactinaemic women had stress-related hyperprolactinaemia as the more likely aetiology. Finally, the frequency of hyperprolactinaemia was similar in users and nonusers of hormonal contraceptives (4·5% and 3·9% respectively, P = 0·209). CONCLUSIONS: The prevalence of hyperprolactinaemia in healthy female blood donors is low and is not influenced by the use of hormonal contraceptives. Pathological causes are very rare with stress-related hyperprolactinaemia and macroprolactinaemia being the most frequent causes of hyperprolactinaemia in these women.

Sexual dimorphism in adipose tissue function as evidenced by circulating adipokine concentrations in the fasting state and after an oral glucose challenge.

STUDY QUESTION: Do the circulating levels of a panel of adipokines involved in glucose metabolism exhibit sexual dimorphism in the fasting state and after an oral glucose load? SUMMARY ANSWER: Our results indicate sexual dimorphism in the circulating concentrations of adipokines involved in intermediate metabolism in the fasting state and during an oral glucose load. This finding suggests an influence of sex steroids on adipose tissue function. WHAT IS KNOWN ALREADY: Sexual dimorphism in adipose tissue distribution fully develops after puberty and modulates the risk for cardiometabolic disorders. However, the possibility that adipose tissue function exhibits sexual dimorphism as well as its distribution is unproved. STUDY DESIGN, SIZE, DURATION: Cross-sectional case-control study including 32 subjects. PARTICIPANTS/MATERIALS, SETTING, METHODS: Sixteen subjects with weight excess (8 men and 8 women, including 4 overweight and 4 obese subjects in each group) and 16 normal weight healthy volunteers (8 men and 8 women) presenting with similar age were submitted to a 75-g oral glucose tolerance test (oGTT). We measured circulating concentrations of insulin, glucose, chemerin, lipocalin-2, omentin-1, leptin and adiponectin and calculated their areas under the oGTT curve (AUC). MAIN RESULTS AND THE ROLE OF CHANCE: Leptin and adiponectin concentrations were higher throughout the oGTT in women compared with men. Lipocalin-2 concentrations decreased during the oGTT in the whole group of study subjects. However, these levels remained higher in men with weight excess compared with normal weight men, whereas in women with weight excess lipocalin-2 levels at the end of the oGTT were lower compared with normal weight women. Sex was among the main determinants of the AUC of omentin-1 and leptin in linear regression models, and lower estradiol and testosterone concentrations were related to higher AUC of chemerin and omentin-1, respectively. Subjects with weight excess had higher AUC of chemerin and leptin and lower AUC of omentin-1 and adiponectin levels, independently of sex. LIMITATIONS, REASONS FOR CAUTION: We included a relatively small sample size and, because this was a cross-sectional study, we cannot infer causality to the associations between the changes in circulating adipokine concentrations and the variables studied here. WIDER IMPLICATIONS OF THE FINDINGS: Sexual dimorphism in adipose tissue function should be considered when studying adiposity and obesity, and also when designing strategies for their diagnosis and management.

Predictive model for autonomous cortisol secretion development in non-functioning adrenal incidentalomas.

PURPOSE: We aimed to develop a predictive model able to stratify patients with non-functioning adrenal incidentalomas (AIs), according to their risk for developing autonomous cortisol secretion (ACS) during follow-up. METHODS: This was a retrospective study of patients with non-functioning AIs consecutively evaluated at a single institution between 2013 and 2019 in whom hormonal follow-up information was available for at least 1 year. Clinical, biochemical, and radiological features were used to build a multivariate Cox regression model using the estimation of all possible equations. RESULTS: We included 331 patients with non-functioning AIs. ACS (post-dexamethasone suppression test (DST) serum cortisol > 1.8 µg/dL) developed in 73 patients during a median follow-up time of 35.7 months [range 12.8-165.4]. The best predictive model for ACS development during follow-up combined age, post-DST serum cortisol, and bilaterality at presentation and showed good diagnostic accuracy (AUC-ROC 0.70 [95% CI 0.65-0.75]). The lowest risk for ACS development was found among patients < 50 years old with cortisol post-DST values < 0.45 µg/dL and with unilateral tumors (risk 2.42%). Baseline post-DST serum cortisol levels at diagnosis were the most important factor for the development of ACS during follow-up (hazard ratio 3.56 for each µg/dL, p < 0.001). The rate of ACS development was associated with post-DST cortisol levels, being 19.2, 32.3, and 68.1 cases/10,000 person-years for patients with baseline post-DST cortisol < 0.9 µg/dL, 0.9-1.3 µg/dL, and > 1.3 µg/dL, respectively. CONCLUSION: After ruling out malignancy, follow-up visits for patients < 50 years old with unilateral non-functioning AIs and post-DST serum cortisol < 0.45 µg/dL are considered unnecessary given the low risk of developing ACS during follow-up.

PCOS during the menopausal transition and after menopause: a systematic review and meta-analysis.

BACKGROUND: Current knowledge about the consequences of PCOS during the late reproductive years and after menopause is limited. OBJECTIVE AND RATIONALE: We performed a systematic review and meta-analysis of data on the pathophysiology, clinical manifestations, diagnosis, prognosis, and treatment of women ≥45 years of age-peri- or postmenopausal-with PCOS. SEARCH METHODS: Studies published up to 15 April 2023, identified by Entrez-PubMed, EMBASE, and Scopus online facilities, were considered. We included cross-sectional or prospective studies that reported data from peri- or postmenopausal patients with PCOS and control women with a mean age ≥45 years. Three independent researchers performed data extraction. Meta-analyses of quantitative data used random-effects models because of the heterogeneity derived from differences in study design and criteria used to define PCOS, among other confounding factors. Sensitivity analyses restricted the meta-analyses to population-based studies, to studies including only patients diagnosed using the most widely accepted definitions of PCOS, only menopausal women or only women not submitted to ovarian surgery, and studies in which patients and controls presented with similar indexes of weight excess. Quality of evidence was assessed using the GRADE system. OUTCOMES: The initial search identified 1400 articles, and another six were included from the reference lists of included articles; 476 duplicates were deleted. We excluded 868 articles for different reasons, leaving 37 valid studies for the qualitative synthesis, of which 28 studies-published in 41 articles-were considered for the quantitative synthesis and meta-analyses. Another nine studies were included only in the qualitative analyses. Compared with controls, peri- and postmenopausal patients with PCOS presented increased circulating total testosterone (standardized mean difference, SMD 0.78 (0.35, 1.22)), free androgen index (SMD 1.29 (0.89, 1.68)), and androstenedione (SMD 0.58 (0.23, 0.94)), whereas their sex hormone-binding globulin was reduced (SMD -0.60 (-0.76, -0.44)). Women with PCOS showed increased BMI (SMD 0.57 (0.32, 0.75)), waist circumference (SMD 0.64 (0.42, 0.86)), and waist-to-hip ratio (SMD 0.38 (0.14, 0.61)) together with increased homeostasis model assessment of insulin resistance (SMD 0.56 (0.27, 0.84)), fasting insulin (SMD 0.61 (0.38, 0.83)), fasting glucose (SMD 0.48 (0.29, 0.68)), and odds ratios (OR, 95% CI) for diabetes (OR 3.01 (1.91, 4.73)) compared to controls. Women with PCOS versus controls showed decreased HDL concentrations (SMD -0.32 (-0.46, -0.19)) and increased triglycerides (SMD 0.31 (0.16, 0.46)), even though total cholesterol and LDL concentrations, as well as the OR for dyslipidaemia, were similar to those of controls. The OR for having hypertension was increased in women with PCOS compared with controls (OR 1.79 (1.36, 2.36)). Albeit myocardial infarction (OR 2.51 (1.08, 5.81)) and stroke (OR 1.75 (1.03, 2.99)) were more prevalent in women with PCOS than controls, the ORs for cardiovascular disease as a whole, coronary artery disease as a whole, breast cancer and age at menopause, were similar in patients and controls. When restricting meta-analysis to studies in which women with PCOS and controls had a similar mean BMI, the only difference that retained statistical significance was a decrease in HDL-cholesterol concentration in the former and, in the two studies in which postmenopausal women with PCOS and controls had similar BMI, patients presented with increased serum androgen concentrations, suggesting that hyperandrogenism persists after menopause, regardless of obesity. WIDER IMPLICATIONS: Hyperandrogenism appeared to persist during the late-reproductive years and after menopause in women with PCOS. Most cardiometabolic comorbidities were driven by the frequent coexistence of weight excess and PCOS, highlighting the importance of targeting obesity in this population. However, the significant heterogeneity among included studies, and the overall low quality of the evidence gathered here, precludes reaching definite conclusions on the issue. Hence, guidelines derived from adequately powered prospective studies are definitely needed for appropriate management of these women.

Is the 1mg-dexamethasone suppression test a precise marker of glucocorticoid excess and cardiometabolic risk in patients with adrenal incidentalomas?

AIM: To analyze if the 1mg-dexamethasone suppression test (DST) is a reliable marker of glucocorticoid excess and cardiometabolic risk in patients with adrenal incidentalomas (AIs). METHODS: Cross-sectional study of patients with nonfunctioning adrenal incidentalomas (NFAIs, defined by cortisol post-DST ≤ 1.8 µg/dL) and patients with autonomous cortisol secretion (ACS, defined by cortisol post-DST > 1.8 µg/Dl). The urinary steroid profile (USP) was determined by gas chromatography coupled to mass spectrometry. Both groups were matched by sex, age and body mass index. RESULTS: Forty-nine patients with AIs (25 with ACS and 24 with NFAI) were included. As a whole, AIs showed a high excretion of ß-cortolone, tetrahydro-11-deoxycortisol (THS), α-cortolone, α-cortol, tetrahydrocortisol (THF) and tetrahydrocortisone (THE). A positive yet modest correlation between post-DST cortisol and total excretion of glucocorticoid metabolites (r = 0.401, P = 0.004) was observed, with the stronger being observed with total THS (r = 0.548, P < 0.001) and THF (r = 0.441, P = 0.002). Some of the metabolites that were elevated in patients with AIs, were higher in patients with ACS-related comorbidities than in those without comorbidities. Post-DST cortisol showed a fair diagnostic accuracy for the prediction of ACS-related comorbidities (AUC 0.767 [95% CI 0.634-0.882]). However, post-DST diagnostic accuracy improved when combined with urinary cortisone, α-cortol, THS and serum DHEAS (0.853 [0.712‒0.954]). CONCLUSION: The DST has a positive, but modest, correlation with urinary glucocorticoid excretion. Similarly, the diagnostic accuracy of the DST for the prediction of ACS-related comorbidities is only fair, but it may be improved if combined with the results of the USP and serum DHEAS. SIGNIFICANCE STATEMENT: This is the first study aimed to evaluate if 1mg-dexamethasone suppression test (DST) is a reliable marker of glucocorticoid excess and cardiometabolic risk in patients with adrenal incidentalomas (AIs) and if urinary steroid profile was measured by GS-MS could improve such a prediction. We found a positive yet modest correlation between post-DST cortisol and total excretion of glucocorticoid metabolites, with the stronger being observed with total tetrahydro-11-deoxycortisol (THS) and tetrahydrocortisol. Post-DST cortisol showed a fair diagnostic accuracy for the prediction of ACS-related comorbidities (AUC 0.767). However, post-DST diagnostic accuracy improved when combined with urinary cortisone, α-cortol, THS and serum DHEAS (0.853).