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.

Pubertad e hiperandrogenismo en niñas y adolescentes con diabetes tipo 1 / Puberty and hyperandrogenism in girls and adolescents with diabetes type 1

Los avances en el tratamiento de la diabetes mellitus tipo 1 han permitido que el desarrollo puberal y la talla final de las niñas y adolescentes con diabetes sean normales aun cuando puedan presentar un discreto retraso en el inicio y la progresión de la telarquia y en la edad de la menarquía. El hirsutismo y las irregularidades menstruales, síntomas asociados al hiperandrogenismo, son identificados con frecuencia y la prevalencia de hiperandrogenismo y de síndrome de ovario poliquístico son mayores en las adolescentes y mujeres con diabetes tipo 1 que en las poblaciones control. Se ha sugerido que el uso de insulina exógena a dosis suprafisiológicas en el tratamiento de la diabetes tipo 1 pueda contribuir al desarrollo del hiperandrogenismo, especialmente por la administración de la insulina por una vía no fisiológica, como es la subcutánea. Por ello resulta obligatoria la identificación de los ´síntomas y signos relacionados con el hiperandrogenismo en el grupo de mujeres con diabetes tipo 1 controladas en nuestras consultas y la introducción de hábitos de vida saludables y la prevención del sobrepeso con objeto de evitar la insulinorresistencia y la utilización de dosis excesivas de insulina en las adolescentes y mujeres jóvenes (AU)

Type 1 diabetic girls and adolescents present with a normal final height and pubertal development due to major advances in the treatment of their disease. However, a mild delay in the age of thelarche and menarche is still observed in some girls with type 1 diabetes. Hirsutism and menstrual disturbances, which are symptoms related to hyperandrogenism, are frequent and prevalence’s of hyperandrogenism, are frequent and prevalence’s of hyperandrogenism and polycystic ovary syndrome are higher in adolescents and young type 1 diabetic women compared with control populations. It has been suggested that the use for supraphysiological doses of exogenous insulin to treat type 1 diabetes might contribute to the development of hyperandrogenism in these patients, especially since insulin is delivered though a non-physiological route such as subcutaneous injection. Therefore, early identification of the symptoms and signs associated with hyperandrogenism is mandatory in the follow-up of type 1 diabetic patients. Healthy life-style recommendations and preventing of weight gain are needed in order to prevent insulin resistance and the use of excessive doses of insulin in the treatment of adolescents and young women (AU)

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.

Etiología del síndrome del ovario poliquístico / Etiology of polycystic ovary syndrome

El síndrome de ovario poliquístico (SOP) es un trastorno endocrinometabólico de etiología compleja. En su fenotipo coinciden pacientes con mecanismos etiopatogénicos diferentes. El defecto primario del SOP parece residir en una capacidad aumentada de secretar andrógenos en el ovario y, posiblemente, la glándula suprarrenal, de etiología aún desconocida. Sobre éste actúan diversos factores desencadenantes, entre los que destacan el hiperinsulinismo endógeno derivado de la resistencia insulínica y la obesidad. Dependiendo de la gravedad del defecto esteroidogénico, los factores desencadenantes tendrán un peso mayor o menor en la aparición del síndrome, como se ejemplifica en las diferencias fenotípicas marcadas entre pacientes delgadas y obesas con SOP. La etiología del SOP es multifactorial y compleja, y en su aparición y desarrollo influyen factores genéticos y ambientales, cuya interrelación es aún objeto de estudio. El escenario más probable es una herencia poligénica sujeta a una influencia ambiental marcada, derivada de factores como la dieta, el sedentarismo y el estilo de vida, sujetos a una marcada variabilidad étnica y geográfica (AU)

The polycystic ovary syndrome (PCOS) is a complex endocrine-metabolic disorder, in which patients with different etiopathogenic mechanisms show the same phenotype. The primary defect in PCOS consists of an exaggerated synthesis and secretion of androgens by the ovary and, possibly, by the adrenal gland. The etiology remains unknown. This primary defect is triggered by several factors, of which the endogenous hyperinsulinism secondary to insulin resistance and obesity is the best known. Depending on the severity of the steroidogenic defect, the triggering factors play a greater or lesser role in the development of the disorder, as exemplified by the marked phenotypic differences among lean and obese PCOS patients. The etiology of PCOS is complex and multifactorial and involves interaction among genetic and environmental factors. This interaction is currently under study. The most probable scenario involves a complex inheritance combined with a strong environmental influence. The latter derives from factors such as diet, exercise, and lifestyle, which are heavily dependent on ethnic and geographic variability (AU)

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.

Hiperandrogenismo en la mujer diabética: rol de laresistencia insulínica y de la hiperinsulinemia / Hyperandrogenism in women with diabetes mellitus: role of insulin resistance and hyperinsulinemia

Desde hace más de 75 años se ha relacionado el hiperandrogenismo con las alteraciones en el metabolismo de los hidratos de carbono y, aunque los mecanismos no se han esclarecido por completo, la resistencia a la insulina juega un papel importante en la patogenia de estas dos enfermedades. El síndrome del ovario poliquístico (SOP) es la enfermedad endocrinológica más frecuente en mujeres en edad fértil y se caracteriza por hiperandrogenismo, oligo o anovulación crónica, hiperinsulinismo y resistencia a la insulina. El hiperinsulinismo puede contribuir al hiperandrogenismo estimulando la síntesis de andrógenos en las células tecales del ovario, reduciendo la síntesis hepática de SHBG (aumentando por tanto la fracción libre de andrógenos circulantes) e interfiriendo en el normal funcionamiento del eje hipotálamo-hipofisogonadal, dando lugar de esta manera a hiperandrogenismo, alteraciones menstruales y anovulación. Además de la resistencia a la insulina y de la frecuente asociación con obesidad, existe una alteración en la función de la célula beta, incluso en ausencia de intolerancia hidrocarbonada, siendo éste un defecto más frecuente en pacientes con historia familiar de diabetes. Este hecho, sumado a la resistencia a la insulina característica del SOP, hace que la incidencia de diabetes mellitus tipo 2 sea más frecuente en este tipo de pacientes. Por otro lado, también existe evidencia a favor de un riesgo aumentado de SOP en pacientes con diabetes mellitus tipo 2.Aunque la diabetes mellitus tipo 1 se caracteriza por una deficiencia absoluta en la secreción de insulina, puede existir un cierto grado de hiperinsulinismo exógeno como resultado de las dosis suprafisiológicas de insulina necesarias para mantener un control metabólico estricto. Como consecuencia de este hiperinsulinismo, podría producirse un aumento en la producción de andrógenos, de tal forma que se ha observado una prevalencia aumentada de manifestaciones hiperandrogénicas en las pacientes con diabetes mellitus tipo 1 (AU)

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.