Influence of state-of-the-art laboratory techniques on the phenotyping of women with polycystic ovary syndrome in the clinical setting.

PURPOSE: Evidence-based guidelines for the management of polycystic ovary syndrome (PCOS) recommend clinical laboratories use liquid chromatography-tandem mass spectrometry (LC-MS/MS) for diagnosing biochemical hyperandrogenism. However, automated immunoassays are still mostly used in routine laboratories worldwide. Another hurdle for PCOS phenotyping in the clinical setting is ultrasound assessment of polycystic ovarian morphology. We address the impact of using state-of-the-art (LC-MS/MS) and of an anti-müllerian hormone (AMH) assay on the diagnosis of PCOS in routine practice. METHODS: In a cross-sectional study, we included 359 premenopausal women consecutively evaluated because of symptoms of functional androgen excess or hyperandrogenemia, and finally diagnosed with PCOS. Patients were submitted to routine phenotyping based on serum androgen measurements by immunoassays and an ovarian ultrasound when necessary. Samples of all patients were also assayed by LC-MS/MS for hyperandrogenemia and for circulating AMH. RESULTS: The observed agreement between immunoassays and LC-MS/MS in identifying hyperandrogenemia was poor [78.0%; k(95%CI): 0.366 (0.283;0.449)]. The observed agreement between ultrasound and increased AMH was 27.3% [(95%CI): 0.060 (0.005; 0.115)]. Using LC-MS/MS changed PCOS phenotypes in 60(15.8%) patients. Fifty-two (18.3%) individuals with hyperandrogenemia by routine immunoassays no longer presented with androgen excess by LC-MS/MS. Overall diagnostic agreement between routine assessment using immunoassays and ultrasound and that derived from LC-MS/MS and the addition of AMH to US was moderate [weighted κ (linear weights): 0.512 (0.416;0.608)]. CONCLUSIONS: Immunoassays used in routine practice are unacceptably inaccurate for phenotyping women with PCOS. Our data cast some doubts upon the interchangeability of serum AMH and ultrasound examination for the diagnosis of PCOS.

Postmenopausal onset of androgen excess: a diagnostic and therapeutic algorithm based on extensive clinical experience.

PURPOSE: Postmenopausal hyperandrogenism is a rare condition that requires identifying those women bearing a life-threatening tumor. We aimed to study diagnostic work-up and management of postmenopausal androgen excess, proposing an algorithm for clinical decision supporting. METHODS: We conducted an observational cross-sectional study and longitudinal follow-up including 51 consecutive menopausal patients reported for hyperandrogenism between 2003 and 2023 to our clinics. We assessed diagnostic testing accuracy and performance by receiver operating characteristic curves, their respective areas under the curve (AUCROC), and 95% confidence intervals (95%CI), for distinguishing between benign and malignant conditions, and androgen excess source. RESULTS: Most commonly, postmenopausal hyperandrogenism derived from benign conditions such as ovarian hyperthecosis (n = 9). However, four (8%) patients had borderline/malignant tumors arising at the ovaries (n = 3) or adrenals (n = 1). These latter were more likely to develop virilization than those with benign disorders [specificity(95%CI)]: 0.87 (0.69; 0.92)]. Circulating total testosterone [AUCROC(95%CI): 0.899 (0.795; 1.000)] and estradiol [AUCROC(95%CI): 0.912 (0.812; 1.000)] concentrations showed good performances for discriminating between both conditions. Transvaginal-ultrasonography found two out of three potentially malignant ovarian neoplasms, and another was apparent on a pelvic computed tomography scan. An adrenal computed tomography scan also located an androgen-secreting carcinoma. CONCLUSIONS: Clinical or biochemical features of an aggressive androgen-secreting tumor should lead to urgently obtaining a targeted imaging. At first, an abdominal-pelvic CT scan represents the best choice to perceive adrenal malignancy, and may identify aggressive ovarian tumors. When warning signs are lacking, a calm and orderly work-up allows properly addressing the diagnostic challenge of postmenopausal hyperandrogenism.

Quantification of lipoproteins by proton nuclear magnetic resonance spectroscopy (1H-NMRS) improves the prediction of cardiac autonomic dysfunction in patients with type 1 diabetes.

AIMS: To assess if advanced characterization of serum glycoprotein and lipoprotein profile, measured by proton nuclear magnetic resonance spectroscopy (1H-NMRS) improves a predictive clinical model of cardioautonomic neuropathy (CAN) in subjects with type 1 diabetes (T1D). METHODS: Cross-sectional study (ClinicalTrials.gov Identifier: NCT04950634). CAN was diagnosed using Ewing's score. Advanced characterization of macromolecular complexes including glycoprotein and lipoprotein profiles in serum samples were measured by 1H-NMRS. We addressed the relationships between these biomarkers and CAN using correlation and regression analyses. Diagnostic performance was assessed by analyzing their areas under the receiver operating characteristic curves (AUCROC). RESULTS: Three hundred and twenty-three patients were included (46% female, mean age and duration of diabetes of 41 ± 13 years and 19 ± 11 years, respectively). The overall prevalence of CAN was 28% [95% confidence interval (95%CI): 23; 33]. Glycoproteins such as N-acetylglucosamine/galactosamine and sialic acid showed strong correlations with inflammatory markers such as high-sensitive C-reactive protein, fibrinogen, IL-10, IL-6, and TNF-α. On the contrary, we did not find any association between the former and CAN. A stepwise binary logistic regression model (R2 = 0.078; P = 0.003) retained intermediate-density lipoprotein-triglycerides (IDL-TG) [ß:0.082 (95%CI: 0.005; 0.160); P = 0.039], high-density lipoprotein-triglycerides (HDL-TGL)/HDL-Cholesterol [ß:3.633 (95%CI: 0.873; 6.394); P = 0.010], and large-HDL particle number [ß: 3.710 (95%CI: 0.677; 6.744); P = 0.001] as statistically significant determinants of CAN. Adding these lipoprotein particles to a clinical prediction model of CAN that included age, duration of diabetes, and A1c enhanced its diagnostic performance, improving AUCROC from 0.546 (95%CI: 0.404; 0.688) to 0.728 (95%CI: 0.616; 0.840). CONCLUSIONS: When added to clinical variables, 1H-NMRS-lipoprotein particle profiles may be helpful to identify those patients with T1D at risk of CAN.

Validation of circulating microRNAs miR-142-3p and miR-598-3p in women with polycystic ovary syndrome as potential diagnostic markers.

STUDY QUESTION: Circulating miRNAs previously associated with androgen excess in women might be used as diagnostic biomarkers for polycystic ovary syndrome (PCOS). SUMMARY ANSWER: Models based on circulating miR-142-3p and miR-598-3p expression show good discrimination among women with and without PCOS, particularly when coupled with easily available measurements such as waist-to-hip ratio (WHR) and circulating LH-to-FSH (LH/FSH) ratios. WHAT IS KNOWN ALREADY: The lack of standardization of the signs, methods, and threshold values used to establish the presence of the diagnostic criteria (hyperandrogenism, ovulatory dysfunction, and polycystic ovarian morphology) complicates the diagnosis of PCOS. Certain biomarkers may help with such a diagnosis. We conducted a validation study to check the diagnostic accuracy for PCOS of several miRNAs that were associated with the syndrome in a small pilot study that had been previously carried out by our research group. STUDY DESIGN, SIZE, DURATION: This was a diagnostic test study involving 140 premenopausal women. PARTICIPANTS/MATERIALS, SETTING, METHODS: We included 71 women with PCOS and 69 healthy control women in the study. Both groups were selected as to be similar in terms of body mass index. We used miRCURY LNA™ Universal RT microRNA PCR to analyse the five miRNAs that had shown the strongest associations with PCOS in a much smaller pilot study previously conducted by our group. We studied diagnostic accuracy using receiver operating characteristics (ROC) curve analysis. MAIN RESULTS AND THE ROLE OF CHANCE: Only the expression of two miRNAs, miR-142-3p and miR-598-3p, of the five studied, was different between the women with PCOS and the non-hyperandrogenic controls. The diagnostic accuracy of the combination of these circulating miRNAs was good (area under the ROC curve (AUC) 0.801; 95% CI: 0.72-0.88) and was further improved when adding WHR (AUC 0.834, 95% CI: 0.756-0.912), LH/FSH ratio (AUC = 0.869, 95% CI: 0.804-0.934) or both (AUC = 0.895, 95% CI: 0.835-0.954). We developed several models by selecting different threshold values for these variables favouring either sensitivity or specificity, with positive and negative predictive values as high as 88% or 85%, respectively. LIMITATIONS, REASONS FOR CAUTION: Patients included here had the classic PCOS phenotype, consisting of hyperandrogenism and ovulatory dysfunction; hence, the present results might not apply to milder phenotypes lacking androgen excess. WIDER IMPLICATIONS OF THE FINDINGS: If confirmed in larger studies addressing different populations and PCOS phenotypes, these biomarkers may be useful to simplify the clinical diagnosis of this prevalent syndrome. STUDY FUNDING/COMPETING INTEREST(S): This research was funded by Instituto de Salud Carlos III, Spanish Ministry of Science and Innovation (grants PI15/01686, PIE16/00050, PI18/01122 & PI21/00116) and co-funded by European Regional Development Fund 'A way to make Europe'. Centro de Investigación Biomédica en Red Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM) and Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS) are also initiatives of the Instituto de Salud Carlos III. The authors have no competing interests to disclose. TRIAL REGISTRATION NUMBER: N/A.

Maximum adenoma diameter, regardless of uni- or bilaterality, is a risk factor for autonomous cortisol secretion in adrenal incidentalomas.

PURPOSE: To evaluate differences between patients with unilateral and bilateral adrenal incidentalomas (AIs) in the prevalence of autonomous cortisol secretion (ACS) and related comorbidities. METHODS: In this multicentre retrospective study, AIs ≥ 1 cm without overt hormonal excess were included in the study. ACS was defined by a post-dexamethasone suppression test (DST) serum cortisol ≥ 5.0 µg/dl, in the absence of signs of hypercortisolism. For the association of ACS with the prevalence of comorbidities, post-DST serum cortisol was also analysed as a continuous variable. RESULTS: Inclusion criteria were met by 823 patients, 66.3% had unilateral and 33.7% bilateral AIs. ACS was demonstrated in 5.7% of patients. No differences in the prevalence of ACS and related comorbidities were found between bilateral and unilateral AIs (P > 0.05). However, we found that tumour size was a good predictor of ACS (OR = 1.1 for each mm, P < 0.001), and the cut-off of 25 mm presented a good diagnostic accuracy to predict ACS (sensitivity of 69.4%, specificity of 74.1%). During a median follow-up time of 31.2 (IQR = 14.4-56.5) months, the risk of developing dyslipidaemia was increased in bilateral compared with unilateral AIs (HR = 1.8, 95% CI = 1.1-3.0 but, this association depended on the tumour size observed at the end of follow-up (HR adjusted by last visit-tumour size = 0.9, 95% CI = 0.1-16.2). CONCLUSIONS: Tumour size, not bilaterality, is associated with a higher prevalence of ACS. During follow-up, neither tumour size nor bilaterality were associated with the development of new comorbidities, yet a larger tumour size after follow-up explained the association of bilateral AIs with the risk of dyslipidaemia.

Postoperative management of patients with pituitary tumors submitted to pituitary surgery. Experience of a Spanish Pituitary Tumor Center of Excellence.

There is a lack of evidence on timing, frequency, and duration of postoperative endocrine, radiologic, and ophthalmologic assessments that should be performed after pituitary surgery (PS). However, it is known that careful optimization of treatment and follow-up strategies as well as a multidisciplinary approach may have a significant impact on long-term outcomes, improving surgical results, minimize complications and facilitate their correct treatment if occurring, and optimize the hormonal, ophthalmological, and radiological reassessment throughout the follow-up. Considering that there are no specific guidelines on the postoperative management of patients with pituitary tumors (PT), we present our protocol for the postoperative management of patients with PT. It has been elaborated by the multidisciplinary team of a Spanish Pituitary Tumor Center of Excellence (PTCE) that includes at least one neurosurgeon, ENT, neuroradiologist, neuro-ophthalmologist, endocrine pathologist and endocrinologist specialized in pituitary diseases. We elaborated this guideline with the aim of sharing our experience with other centers involved in the management of PT thereby facilitating the postoperative management of patients submitted to PS.

Beneficial changes on plasma apolipoproteins A and B, high density lipoproteins and oxidized low density lipoproteins in obese women after bariatric surgery: comparison between gastric bypass and sleeve gastrectomy.

BACKGROUND: The beneficial effects in lipid profiles after obesity surgery might be associated with the decrease in cardiovascular risk. However, direct comparison between different surgical techniques has not been extensively performed. METHODS: In the present study we compare 20 obese women submitted to laparoscopic Roux en Y gastric bypass (RYGB) with 20 women submitted to sleeve gastrectomy (SG). Twenty control women matched for age and baseline cardiovascular risk were also included. Both patients and controls were followed up for 1 year after surgery or conventional treatment with diet and exercise, respectively. Lipid profiles were measured at baseline, 6 and 12 months later. Carotid intima-media thickness was measured by ultrasonography at baseline and at the end of the study. RESULTS: Women submitted to bariatric surgery showed a decrease in total cholesterol, triglycerides, oxidized-LDL and ApoB, and an increase in HDL and ApoA concentrations that occurred regardless of the surgical procedure. LDL concentrations, however, decreased only after RYGB whereas Lp(a) showed no changes. We did not observe any correlation between the changes in serum lipid concentrations and those in carotid intima-media thickness. CONCLUSIONS: Sleeve gastrectomy and gastric bypass induce a similar beneficial effect on serum lipids in women with high cardiovascular risk 1 year after surgery.

The R453Q and D151A polymorphisms of hexose-6-phosphate dehydrogenase gene (H6PD) influence the polycystic ovary syndrome (PCOS) and obesity.

Hexose-6-phosphate dehydrogenase (H6PDH) influences 11ß-hydroxysteroid dehydrogenase activity, a key enzyme in the peripheral metabolism of cortisol that modulates insulin sensitivity in adipose tissue. To study the associations of R453Q and D151A polymorphisms in the H6PDH gene (H6PD) with polycystic ovary syndrome (PCOS) and their influence on clinical and metabolic variables, we genotyped 237 patients with PCOS and 135 control women for the R453Q (rs6688832) and D151A (rs34603401) variants in H6PD. The R453Q genotypes were distributed differently in patients and controls (χ(2)=9.55, P=0.002). Genotypes of D151A were distributed evenly in women with PCOS and controls, but showed a different distribution in non-obese and obese women (χ(2)=3.95, P=0.047), especially within the PCOS subgroup (χ(2)=4.65, P=0.031). A backward stepwise likelihood ratio logistic regression model (Nagelkerke's R(2)=0.490; χ(2)=164; P<0.0001) retained free testosterone (OR=1.13; 95% CI: 1.10-1.17) and H6PD Q453 alleles (OR=0.46; 95% CI: 0.27-0.79) as statistically significant predictors for PCOS, whereas homeostasis model assessment of insulin resistance and the H6PD D151A variant were excluded by the model. Both H6PD variants were associated with several phenotypic variables, including fasting insulin, homeostasis model assessment of insulin resistance and androstenedione levels. In summary, the R453Q and D151A variants of the H6PD gene are associated with PCOS and obesity, respectively, and may contribute to the PCOS phenotype by influencing obesity, insulin resistance and hyperandrogenism.

Epidemiology, diagnosis and management of hirsutism: a consensus statement by the Androgen Excess and Polycystic Ovary Syndrome Society.

BACKGROUND: Hirsutism, defined by the presence of excessive terminal hair in androgen-sensitive areas of the female body, is one of the most common disorders in women during reproductive age. METHODS: We conducted a systematic review and critical assessment of the available evidence pertaining to the epidemiology, pathophysiology, diagnosis and management of hirsutism. RESULTS: The prevalence of hirsutism is ~10% in most populations, with the important exception of Far-East Asian women who present hirsutism less frequently. Although usually caused by relatively benign functional conditions, with the polycystic ovary syndrome leading the list of the most frequent etiologies, hirsutism may be the presenting symptom of a life-threatening tumor requiring immediate intervention. CONCLUSIONS: Following evidence-based diagnostic and treatment strategies that address not only the amelioration of hirsutism but also the treatment of the underlying etiology is essential for the proper management of affected women, especially considering that hirsutism is, in most cases, a chronic disorder needing long-term follow-up. Accordingly, we provide evidence-based guidelines for the etiological diagnosis and for the management of this frequent medical complaint.

Application of proteomics to the study of polycystic ovary syndrome.

BACKGROUND: Clinical proteomics consists of qualitative and quantitative profiling of proteins present in clinical specimens such as body fluids or tissues, with the aim of discovering novel proteins and cellular pathways associated with the disease of interest. AIM: To review the proteomic studies conducted to date that addressed different aspects of the pathogenesis of polycystic ovary syndrome (PCOS). METHODS: Descriptive review of studies that applied proteomic techniques to the study of PCOS. Published articles were identified using the Entrez-PubMed online search facilities. RESULTS: Most studies conducted to date focused on protein variations in plasma and different target tissues. Plasma proteomics analysis revealed that PCOS associates changes in protein expression in several acute-phase response proteins. Moreover, some of these molecules play major roles in iron metabolism and low-grade chronic inflammation. Studies using omental adipose tissue from morbidly obese women with or without PCOS revealed differences in abundance of proteins that may be involved in lipid and glucose metabolism, oxidative stress processes, and adipocyte differentiation. Moreover, identification of differentially expressed proteins in ovarian tissue, granulosa cells or T lymphocites may help to characterize more clearly some aspects of this disorder. CONCLUSIONS: Although the application of proteomic techniques to the study of PCOS is in its early infancy, studies conducted to date highlight its heterogeneous nature. Aside from androgen excess, several pathways related to intermediate metabolism, oxidative stress processes, inflammation and iron metabolism appear to be involved in the pathophysiology of PCOS.

Treatment of polycystic ovary syndrome (PCOS) with metformin ameliorates insulin resistance in parallel with the decrease of serum interleukin-6 concentrations.

Low-grade chronic inflammation underlies the pathogenesis of insulin-resistant disorders such as polycystic ovary syndrome (PCOS). We aimed to study if the changes observed in the insulin sensitivity of PCOS patients during treatment with oral contraceptives or metformin associate changes in the serum inflammatory markers interleukin-6 (IL-6) and interleukin-18 (IL-18). In a randomized open-label clinical trial (NLM Identifier NCT00428311), 34 PCOS patients were allocated to receive oral treatment with metformin (850 mg twice daily) or with the Diane (35) Diario contraceptive pill (35 µg of ethynylestradiol plus 2 mg of cyproterone acetate) for 24 weeks. Changes in serum IL-6 and IL-18 levels and insulin sensitivity index were monitored throughout the study. Eighteen women without hyperandrogenism served as controls for serum interleukin concentrations. PCOS women treated with metformin showed a decrease in IL-6 levels throughout the study compared with women treated with Diane (35) Diario (-33% change vs. +23% change, F=3.709, p=0.048; intention-to-treat analysis: F=5.569, p=0.011). There were no statistically significant changes in IL-18 concentrations with any treatment. The decrease in IL-6 levels in women receiving metformin occurred in parallel to the increase in the insulin sensitivity index (r=-0.579, p=0.048; intention-to-treat analysis, r=-0.687, p=0.001). In conclusion, serum IL-6 levels decreased during treatment with metformin in parallel to amelioration of insulin resistance, whereas oral contraceptives slightly increased circulating IL-6 levels without changing insulin sensitivity. Both drugs had a neutral effect on serum IL-18 concentrations.

Obesity and the polycystic ovary syndrome.

The polycystic ovary syndrome (PCOS) is a mostly hyperandrogenic disorder and is possibly the most common endocrinopathy of premenopausal women. The primary defect in PCOS appears to be an exaggerated androgen synthesis and secretion by the ovaries and the adrenal glands. In a substantial proportion of PCOS patients, the primary defect in androgen secretion is triggered by factors such as the hyperinsulinism resulting from insulin resistance and/or the secretion of metabolically active substances by visceral adipose tissue, because these factors may facilitate androgen synthesis at the ovaries and the adrenals of predisposed women. The prevalence of obesity in PCOS patients is increased when compared to the general female population and, conversely, the prevalence of PCOS is increased in overweight and obese women when compared to their lean counterparts. Obesity exerts a major impact on the PCOS phenotype, particularly on the metabolic associations and complications of the syndrome. Among others, the presence obesity is clearly related to the infertility of PCOS, and increases the risk for the metabolic syndrome and its constellation of cardiovascular risk factors in these women. This review will summarize the pathophysiological mechanisms underlying the association of obesity and PCOS, the impact of obesity on the PCOS phenotype and on the association of PCOS with metabolic disorders and cardiovascular risk factors, and the new developments in the management of obese PCOS patients.

Reproductive outcome of women with 21-hydroxylase-deficient nonclassic adrenal hyperplasia.

CONTEXT: Because many women with 21-hydroxylase (21-OH)-deficient nonclassic adrenal hyperplasia (NCAH) carry at least one allele affected by a severe mutation of CYP21, they are at risk for giving birth to infants with classic adrenal hyperplasia (CAH). OBJECTIVE: Our objective was to determine the frequency of CAH and NCAH infants born to mothers with 21-OH-deficient NCAH. DESIGN AND SETTING: We conducted an international multicenter retrospective/prospective study. PATIENTS AND METHODS: The outcome of 203 pregnancies among 101 women with 21-OH-deficient NCAH was reviewed. The diagnosis of 21-OH-deficient NCAH was established by a basal or post-ACTH-stimulation 17-hydroxyprogesterone level of more than 10 ng/ml (30.3 nmol/liter). When possible, genotype analyses were performed to confirm CAH or NCAH in the offspring. RESULTS: Of the 203 pregnancies, 138 (68%) occurred before the mother's diagnosis of NCAH and 65 (32%) after the diagnosis. Spontaneous miscarriages occurred in 35 of 138 pregnancies (25.4%) before the maternal diagnosis of NCAH, and in only four of 65 pregnancies (6.2%) after the diagnosis (P < 0.002). Four (2.5%; 95% confidence interval, 0.7-6.2%) of the 162 live births were diagnosed with CAH. To date, 24 (14.8%; 95% confidence interval, 9.0-20.6%) children, 13 girls and 11 boys, have been diagnosed with NCAH. The distribution of NCAH children and their mothers varied significantly by ethnicity (P < 0.0001, for both). CONCLUSIONS: The risk of a mother with 21-OH-deficient NCAH for giving birth to a child affected with CAH is 2.5%; at least 14.8% of children born to these mothers have NCAH.

Adiponectin and resistin in PCOS: a clinical, biochemical and molecular genetic study.

BACKGROUND: We conducted a cross-sectional case-control study to evaluate the possible involvement of adiponectin and resistin in the pathogenesis of polycystic ovary syndrome (PCOS). METHODS: Seventy-six PCOS patients and 40 non-hyperandrogenic women matched for BMI and degree of obesity were included. Serum adiponectin and resistin levels, anthropometrical and hormonal variables, the 45 T-->G and 276 G-->T polymorphisms in the adiponectin gene, and the -420 C-->G variant in the resistin gene, were analysed. RESULTS: Serum adiponectin concentrations were reduced in PCOS patients compared with controls (P = 0.038) irrespective of the degree of obesity, whereas serum resistin levels were increased in overweight and obese women compared with lean subjects (P = 0.016), irrespective of their PCOS or controls status. The adiponectin and resistin polymorphisms were not associated with PCOS and did not influence serum levels of adiponectin, resistin and other clinical and hormonal variables. In a multiple regression model, the waist-to-hip ratio, free testosterone levels and age, but not insulin resistance, were the major determinants of hypoadiponectinaemia. CONCLUSIONS: PCOS patients present with hypoadiponectinaemia, in relation with abdominal adiposity and hyperandrogenism. Our present results suggest that hyperandrogenism and abdominal obesity, by reducing the serum levels of the insulin sensitizer adipokine adiponectin, might contribute to the insulin resistance of PCOS.

Weight gain and cardiovascular risk factors during smoking cessation with bupropion or nicotine.

Weight gain is frequent after smoking cessation, and may limit patient's will to quit and long-term success. Nicotine and bupropion are effective drugs for smoking withdrawal. However, their influence on weight gain, insulin resistance and other cardiovascular risk factors, as well as possible differences in obese and lean subjects, have not been fully evaluated. We randomised 25 lean and 25 obese smokers to receive either bupropion or nicotine patches. Clinical evaluation and lipid profile were performed at baseline and after treatment. Insulin resistance was also assessed at the end. Weight, BMI, waist-to-hip ratio, and diastolic blood pressure increased (p < 0.005), whereas lipid profile improved (p < 0.001) after smoking cessation independently of obesity at baseline or drug used. Obese patients had higher insulin resistance at the end (p < 0.05) regardless of drug used. Weight gain was inversely related to age (beta= - 0.125, R = 0.38, p = 0.046), and insulin resistance was related to obesity at baseline (beta = 0.85, R = 0.46, p = 0.02). In conclusion, weight gain after smoking cessation is not dependent on obesity or drug taken. A beneficial lipid profile is achieved after quitting smoking with either bupropion or nicotine patch in both obese and lean subjects.

Obesity, and not insulin resistance, is the major determinant of serum inflammatory cardiovascular risk markers in pre-menopausal women.

AIMS/HYPOTHESIS: Increased serum inflammatory markers have been found in obesity and insulin-resistant states, and could play a causative role in insulin resistance, atherosclerosis and cardiovascular disease. The polycystic ovary syndrome represents a human model of insulin resistance because both lean and obese polycystic ovary syndrome patients are insulin-resistant compared with non-hyperandrogenic women. We evaluated whether obesity, insulin resistance, or both, are related to the increased concentrations of inflammatory markers in pre-menopausal women. METHODS: We compared 35 patients with polycystic ovary syndrome and 28 healthy women, paired for BMI, prevalence of obesity and smoking. Measurements included serum inflammatory markers, BMI, waist-to-hip ratio, blood pressure, serum glucose, insulin, lipid and hormone concentrations, and insulin sensitivity index. RESULTS: The insulin sensitivity index was reduced in polycystic ovary syndrome patients compared with controls. However, no differences were observed between both groups in C-reactive protein, interleukin 6, tumour necrosis factor-alpha, soluble type 2 tumour necrosis factor receptor, and soluble intercellular cell adhesion molecule-1. When considering patients and controls as a whole, C-reactive protein and interleukin 6, were increased in obese subjects compared with lean women. Inverse correlations existed between insulin sensitivity index and C-reactive protein, interleukin 6, tumour necrosis factor-alpha, soluble type 2 tumour necrosis factor receptor, and soluble intercellular cell adhesion molecule-1. Only the weak correlation with C-reactive protein persisted after controlling for BMI. CONCLUSION/INTERPRETATION: Obesity, and not insulin resistance, is the major determinant of serum inflammatory cardiovascular risk markers in pre-menopausal women.

Quality of life and psychometric functionality in patients with differentiated thyroid carcinoma.

We studied the psychological performance and the quality of life in patients with differentiated thyroid carcinoma, either during treatment with chronic suppressive doses of levothyroxine, or during the withdrawal of levothyroxine needed to perform whole-body scanning with radioactive iodine, with those of appropriate healthy controls. Eighteen women with differentiated thyroid carcinoma and 18 euthyroid age-matched healthy women were recruited. Patients were studied the day before levothyroxine withdrawal (when in chronic mild or subclinical hyperthyroidism), 4-7 days later (when most patients had normal serum free thyroxine and free triiodothyronine levels), and the day before scanning (when in profound hypothyroidism). Controls were studied at one time point. When compared with controls, patients presented with impairment of several indexes during chronic suppressive levothyroxine therapy (total score, emotional, sleep, energy and social of the Nottingham Health Profile; mental health, general health and social function of the SF-36, and total score on Wais Digit Span; P<0.05 for all comparisons). Also, quality of life indexes (19 of 21 scores), cognitive tests (6 of 12 scores), and affective and physical symptoms visual mental scales (18 of 19) worsened during profound hypothyroidism (P<0.05 for all comparisons). Quality of life and cognitive performance were almost comparable with those of euthyroid controls when most patients had normal free thyroxine and triiodothyronine levels. In conclusion, quality of life and psychometric functionality in patients with differentiated thyroid carcinoma is not only affected by withdrawal of levothyroxine but also by long-term treatment with supraphysiological doses of levothyroxine.

Receiver operating characteristic analysis of the performance of basal serum hormone profiles for the diagnosis of polycystic ovary syndrome in epidemiological studies.

OBJECTIVE: We have used receiver operating characteristic (ROC) analysis to determine the diagnostic performance of several serum parameters, in order to evaluate their potential usefulness in establishing the diagnosis of polycystic ovary syndrome (PCOS) in epidemiological studies. DESIGN: Prospective study. METHODS: One hundred and fourteen women reporting spontaneously for blood donation were included in the study. Menopausal and oral contraceptive-treated women were excluded. Serum samples were obtained at the moment of donation, independently of fasting, time of day or day of menstrual cycle. Measurements included total testosterone, sex hormone-binding globulin (SHBG), dehydroepiandrosterone sulfate (DHEAS), LH, FSH and estradiol. The free testosterone (FT) concentration and the free androgen index (FAI) were calculated from testosterone and SHBG levels. ROC curves were calculated for all these serum determinations. RESULTS: Eight patients were diagnosed with PCOS, according to the presence of oligomenorrhea, hirsutism, acne and/or hyperandrogenemia, and exclusion of non-classic congenital adrenal hyperplasia, hypothyroidism and hyperprolactinemia. Of the parameters studied SHBG, FAI, FT and DHEAS were considered adequate measures for the diagnosis of PCOS. For example, serum SHBG levels showed an area under the ROC curve of 0.875+/-(S.E.(w))0.045 (95% confidence interval 0.800-0.929). A SHBG decision threshold <37 nmol/l had a sensitivity of 87.5%, a specificity of 86.8%, a positive likelihood ratio of 6.63, and a negative likelihood ratio of 0.14, for the diagnosis of PCOS. CONCLUSIONS: Our present results strongly suggest that decreased SHBG levels, and increased FAI, free testosterone concentration and DHEAS concentrations, are highly effective as single analytical procedures in epidemiological studies for the detection of PCOS in women of reproductive age.

TNF-alpha and hyperandrogenism: a clinical, biochemical, and molecular genetic study.

To evaluate the role of TNF-alpha in the pathogenesis of hyperandrogenism, we have evaluated the serum TNF-alpha levels, as well as several polymorphisms in the promoter region of the TNF-alpha gene, in a group of 60 hyperandrogenic patients and 27 healthy controls matched for body mass index. Hyperandrogenic patients presented with mildly increased serum TNF-alpha levels as compared with controls (mean[median] +/- SD: 7.2[7.0] +/- 3.3 pg/ml vs. 5.6[4.4] +/- 4.0 pg/ml, P < 0.02). Although no differences in body mass index and insulin resistance indexes were observed between patients and controls, when subjects were classified by body weight, serum TNF-alpha was increased only in lean patients as compared with lean controls, but this difference was not statistically significant when comparing obese patients with obese controls. The TNF-alpha gene polymorphisms studied here (-1196C/T, -1125G/C, -1031T/C, -863C/A, -857C/T, -316G/A, -308G/A, -238G/A, and -163G/A) were equally distributed in hyperandrogenic patients and controls. However, carriers of the -308A variant presented with increased basal and leuprolide-stimulated serum androgens and 17-hydroxyprogesterone levels when considering patients and controls as a group. No differences were observed in serum TNF-alpha levels, body mass index, and insulin resistance indexes, depending on the presence or absence of these variants. In conclusion, our present results suggest that the TNF-alpha system might contribute to the pathogenesis of hyperandrogenism, independent of obesity and insulin resistance. However, elucidation of the precise mechanisms underlying the relationship between the TNF-alpha system and androgen excess is needed before considering TNF-alpha as a significant contributing factor to the development of hyperandrogenism.