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.

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.

Impact of smoking cessation on estimated cardiovascular risk in Spanish type 2 diabetes mellitus patients: The DIABETES study. / Impacto de la cesación tabáquica en el riesgo cardiovascular estimado de pacientes con diabetes mellitus tipo 2: El estudio DIABETES.

AIMS: To assess the cardiovascular risk according to the UKPDS risk engine; Framingham function and score comparing clinical characteristics of diabetes mellitus type 2 (DM2) patients according to their habits status. PATIENTS AND METHODS: A descriptive analysis was performed. A total of 890 Spanish patients with DM2 (444 smokers and 446 former-smokers) were included in a cross-sectional, observational, epidemiological multicenter nationwide study. Coronary heart disease risk at 10 years was calculated using the UKPDS risk score in both patient subgroups. Results were also compared with the Spanish calibrated (REGICOR) and updated Framingham risk scores. RESULTS: The estimated likelihood of coronary heart disease risk at 10 years according to the UKPDS score was significantly greater in smokers compared with former-smokers. This increased risk was greater in subjects with poorer blood glucose control, and was attenuated in women ≥60 years-old. The Framingham and UKPDS scores conferred a greater estimated risk than the REGICOR equation in Spanish diabetics. CONCLUSIONS: Quitting smoke in patients with DM2 is accompanied by a significant decrease in the estimated risk of coronary events as assessed by UKPDS. Our findings support the importance of quitting smoking among diabetic patients in order to reduce cardiovascular risk.

Somatotroph tumor progression during pegvisomant therapy: a clinical and molecular study.

CONTEXT: There is concern that pegvisomant could be associated with a higher risk of tumor growth. The rate and possible determinants of this tumor growth are unknown. OBJECTIVE: The objective of the study was to investigate the clinical, immunohistological, and molecular factors conditioning tumor growth in patients taking pegvisomant. DESIGN AND SETTING: This was a cross-sectional study performed from 2004 to 2010 in four university hospitals in Spain. PATIENTS: Seventy-five acromegalic patients with active disease resistant to somatostatin analogs treated with pegvisomant were followed up for a mean of 29 ± 20 months. MAIN OUTCOME MEASURES: Magnetic resonance images before initiation of pegvisomant, at 6 months, and then yearly were examined in all patients. Immunohistological and molecular studies were performed in tumors that grew. RESULTS: A significant increase in tumor size was observed in five patients (6.7%). Absence of previous irradiation (P = 0.014) and shorter duration of prepegvisomant somatostatin analog therapy (P < 0.001) were associated with an increased risk of tumor growth. A stepwise multivariate linear regression analysis (R(2) = 0.334, P < 0.001) identified the duration of somatostatin analog therapy prior to pegvisomant (beta = -4.509, P = 0.014) as the only significant predictor of tumor growth. In those tumors that grew, GH expression and insulin receptor expression were higher (P = 0.033 in both cases) than in the control group. CONCLUSIONS: No previous radiotherapy, shorter duration of prepegvisomant somatostatin analog therapy, and higher tumor expression of GH and insulin receptor could be risk factors for tumor growth during pegvisomant therapy.

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.

The efficacy of octreotide LAR as firstline therapy for patients with newly diagnosed acromegaly is independent of tumor extension: predictive factors of tumor and biochemical response.

Surgical outcome of acromegaly depends on the preoperatory tumor size and extension. Somatostatin analogues are also a highly effective treatment for acromegalic patients. Nevertheless, the response of GH-secreting adenomas to primary medical therapy is variable. The aim of the present study was to evaluate the efficacy of octreotide LAR as primary therapy for acromegalic patients as a function of initial tumor extension. We performed a multicentre, prospective, observational and analytical study recruiting 19 "naive" acromegalic patients (5 microadenomas, 10 intrasellar, and 4 extrasellar macroadenomas). All of them were treated with octreotide LAR for 12 months. Basal GH and fasting IGF-I concentrations, and tumor volume were measured at baseline and after 6 and 12 months of treatment. Six patients withdrew the study. The patients who completed the protocol showed a significant reduction of tumor volume (25+/-23%, Wilk's lambda=0.506, F=4.400, p=0.046) independently of tumor extension at study entry (Wilk's lambda=0.826, F=0.452, p=0.769). A shrinkage >25% of baseline tumor volume was achieved in 8 (42%) patients with no differences between tumor extension subgroups. Basal GH levels (76+/-18%) and fasting IGF-I (52+/-31%) decreased throughout the study. Six (46%) patients normalized their IGF-I levels. Octreotide LAR is an effective first-line treatment for a large group of acromegalic patients independent of initial tumor extension.

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.

Cost of management of invasive growth hormone-secreting macroadenoma.

BACKGROUND: At the time of diagnosis, macroadenomas represent 60-80% of GH secreting adenomas, of which 25-30% are invasive macroadenomas. These aggressive tumors have the worst surgical success rates in terms of cure, and often need several therapeutic approaches in order to control disease status. Acromegalic patients are subject to increased mortality and important health resource consumption related to their associated co-morbidities, in addition to the costs that are related to diagnosis itself and initial treatment of the disease. OBJECTIVE: Assessment of the cost of initial management and outcome of acromegalic patients with invasive pituitary adenomas. STUDY DESIGN: Retrospective and observational study of review of records. SETTING: Two tertiary hospitals. PATIENTS: 11 consecutive patients between 18 and 80 yr old diagnosed with acromegaly due to an invasive pituitary macroadenoma. INTERVENTION: Collection of data of biochemical and radiological tests, specialist visits, hospitalisation, surgery, pharmacological and radiotherapy treatment at diagnosis and over 4 yr of follow-up after initial treatment. Costs were evaluated using the data of the Centre for Health Economics and Social Policy Studies and the Official College of Pharmacists of Spain. MAIN OUTCOME MEASURE: Global and patient/yr follow-up costs of illness. RESULTS: The mean costs for acromegaly for the period of follow-up ranged from 7,072 to 9,874 euro/patient/yr, for biochemically non-controlled (no.=6) and controlled patients (no.=5) respectively. The most important cost in the perioperative period was for admission in the intensive care unit. After surgery, SS analogues were the principal contributors to the economic burden. CONCLUSION: In this paper we have for the first time presented a pharmacoeconomic study of GH secreting invasive macroadenoma. The poor prognosis of our cohort of patients and the higher rate of controlled patients and normal IGF-I levels warrant the employment of multiple therapeutic options. The cost associated with this treatment in this complex disease of low prevalence is not excessive and can be supported by healthcare services.

[Hungry bone syndrome related to hyperthyroidism]. / Síndrome del hueso hambriento relacionado con hipertiroidismo.

Hungry bone syndrome is a common clinical entity which is accompanying of hypocalcemia, hypomagnesemia, and hipophosphatemia, results from an increase in bone formation. It is related to a pathological scenario which causes an imbalance between osteoclast-mediated bone resorption and osteoblast-mediates bone formation, favouring the latter. Its classic presentation occurs after parathyroidectomy in hyperparathyroydism's patients. Its clinical features are largely due to plasmatic calcium levels reduction. Hungry bone syndrome is frequent in hyperparathyroid's patients who have development bone disease before surgery. Even less frequent, it has also been described after thyroydectomy in patients with hyperthyroidism. We hereby report a case of hungry bone syndrome in one patient who suffers a Graves' disease. Then, we will provide a brief review of pathogenesis and therapeutic features.

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.