Respuesta a metformina en el síndrome de ovario poliquístico (SOP): rol de las variantes genéticas / Response to metformin in polycystic ovary syndrome (PCOS): role of genetic variants

La metformina es un hipoglicemiante ampliamente utilizado en el tratamiento de mujeres con síndrome de ovario poliquístico (SOP) por su acción como sensibilizante a la insulina, demostrando tener múltiples efectos favorables en parámetros clínicos y bioquímicos. Especial interés ha causado la variabilidad interindividual en el tratamiento con metformina, que se manifiesta con una respuesta subóptima en diversos grados o con la presencia de efectos adversos, principalmente gastrointestinales. Hasta ahora, pocos estudios han caracterizado este fenómeno en el SOP, así como los mecanismos que le subyacen. Se ha propuesto que variantes de genes envueltos en el transporte y acción de metformina podrían contribuir a la heterogeneidad de su respuesta. En este sentido, se han identificado polimorfismos de nucleótidos únicos (SNPs) en los transportadores de cationes orgánicos, en las proteínas de extrusión de múltiples fármacos y toxinas, y en proteínas quinasas; cuyas principales acciones son a nivel intestinal, hepático y renal, afectando la absorción, distribución y excreción de metformina, probablemente por modificaciones en su farmacocinética. Hasta ahora los escasos estudios disponibles en el SOP han identificado SNPs que estarían afectando la eficacia del tratamiento, sin embargo, no se ha profundizado en los efectos adversos asociados a las variantes genéticas. Es evidente que dichas variantes tienen relevancia clínica y que debieran ser consideradas al diseñar un tratamiento farmacológico, para optimizar su efectividad y minimizar reacciones adversas. El objetivo de este artículo es revisar la información sobre las variantes genéticas asociadas a la variabilidad en la respuesta del tratamiento con metformina en el SOP.

Metformin is a hypoglycemic agent widely used in the treatment of women with Polycystic Ovary Syndrome (PCOS) due to its action as an insulin sensitizer and its multiple favorable effects on clinical and biochemical parameters. There is great concern regarding the inter-individual variability in the response to metformin treatment, which may manifest as a suboptimal effect to varying degrees or by the presence of adverse effects, mainly gastrointestinal. Until now, scarce studies have characterized this phenomenon in PCOS, as well as the mechanisms that underlie it. It has been proposed that genetic variants involved in metformin transport and action could contribute to the heterogeneity of its response. In this sense, single nucleotide polymorphisms (SNPs) have been identified in organic cation transporters, in multidrug and toxin extrusion proteins, and in protein kinases; whose main actions are at the intestinal, hepatic and renal levels, affecting the absorption, distribution and excretion of metformin, probably due to modifications in the pharmacokinetics of the drug. Until now, the few studies available on PCOS have identified SNPs that may be affecting the efficacy of the treatment. However, the adverse effects associated with genetic variants have not been studied in depth. These variants may have clinical relevance and should be considered when designing a pharmacological treatment, to optimize its effectiveness and minimize adverse reactions. The objective of this article is to review the information on genetic variants associated with variability in the response to metformin treatment in PCOS.

Prenatal androgen exposure and transgenerational susceptibility to polycystic ovary syndrome.

How obesity and elevated androgen levels in women with polycystic ovary syndrome (PCOS) affect their offspring is unclear. In a Swedish nationwide register-based cohort and a clinical case-control study from Chile, we found that daughters of mothers with PCOS were more likely to be diagnosed with PCOS. Furthermore, female mice (F0) with PCOS-like traits induced by late-gestation injection of dihydrotestosterone, with and without obesity, produced female F1-F3 offspring with PCOS-like reproductive and metabolic phenotypes. Sequencing of single metaphase II oocytes from F1-F3 offspring revealed common and unique altered gene expression across all generations. Notably, four genes were also differentially expressed in serum samples from daughters in the case-control study and unrelated women with PCOS. Our findings provide evidence of transgenerational effects in female offspring of mothers with PCOS and identify possible candidate genes for the prediction of a PCOS phenotype in future generations.

Higher luteinizing hormone levels associated with antimüllerian hormone in postmenarchal daughters of women with polycystic ovary syndrome.

OBJECTIVE: To study the reproductive and metabolic differences between daughters of women with polycystic ovary syndrome (PCOSd) and control women (Cd) after menarche. DESIGN: Case-control study. SETTING: Clinical endocrinology unit. PATIENT(S): We studied 43 PCOSd and 28 Cd 1.5-6 years after menarche. INTERVENTION(S): Determination of anthropometry, pubertal development, hirsutism, oral glucose tolerance test, and GnRH analogue test. MAIN OUTCOME MEASURE(S): Ferriman score, sex steroids, gonadotropins, antimüllerian hormone (AMH), ovarian volumes, and glucose and insulin levels. RESULT(S): The groups were similar in chronologic, gynecologic, and menarchal ages and anthropometric variables. Ferriman score, ovarian volumes, and AMH were higher in PCOSd. Propensity score analysis showed that there were significant differences in LH, LH-FSH ratio, T and free androgen index, post-stimulated LH and LH-FSH ratio, and 2-hour insulin that could be attributed only to the fact of being a PCOS daughter. The generalized linear model showed that higher LH levels were positively associated with AMH and T levels. CONCLUSION(S): We found that higher LH, androgen, and insulin levels are present in PCOSd during the postmenarchal period, which may establish the basis for the development of PCOS during adulthood. Moreover, LH levels were associated with AMH levels, which supports that the neuroendocrine feedback proposed for AMH and LH is present in humans and that this feature is probably programed in utero, as recently shown in mice.

Compromiso de seno cavernoso como presentación de cáncer anaplásico de tiroides / Cavernous sinus involvement as presentation of anaplastic thyroid cancer

Anaplastic thyroid cancer is an uncommon malignant tumor, usually fatal, primarily affecting older adults and doesn't have effective systemic therapy. The median survival is less than 6 months from diagnosis. Brain metastases are low frequency and reach 18 percent. We present the case of a patient with papillary carcinoma of the thyroid who takes an aggressive form, becoming anaplastic carcinoma, with involvement of the central nervous system (CNS) manifested by paralysis of the cranial nerve IV, which is rare clinical condition.

Cáncer diferenciado de tiroides en tiroides lingual, presentación de un caso / Differentiated thyroid cancer in the lingual thyroid, presentation of a case

The lingual thyroid carcinoma is very uncommon neoplasia with an incidence of less than 1 percent. The papillary variant is the most frequent. Cervical MRI helps differentiate muscle from thyroid tissue. The definitive diagnosis is given by histology. Management is similar to that of orthotopic thyroid cancer. We present the case of a 23-year-old woman with hypothyroidism undergoing treatment with dysphagia and sensation of pharyngeal foreign body and malodorous oral bleeding. Nasopharyngoscopy showed a rounded mass at the base of the tongue; the biopsy was compatible with thyroid neoplasia. Image study with ultrasound confirms empty thyroid bed with presence of lingual ectopic thyroid. The team of surgeons performed surgery with Trotter Technique, they removed a tumor of 4 centimeters of diameter. The definitive biopsy concludes minimally invasive follicular carcinoma. The treatment was completed with 100 mCi of radioiodine. Systemic screening at 7 days was negative, as the post-operative thyroglobulin (Tg)

[Effects of pregnancy and changes in body weight on polycystic ovary syndrome phenotypes according to the Rotterdam criteria]. / Clasificación de los fenotipos de síndrome de ovario poliquístico de acuerdo a los criterios de Rotterdam: ¿una condición estática o variable?

BACKGROUND: Polycystic Ovary Syndrome (PCOS) is tightly associated with insulin resistance and obesity and characterized by hyperandrogenism, chronic oligo-anovulation and polycystic ovarian morphology when fully expressed. The 2003 Rotterdam consensus proposed that two or three of these features were necessary to make the diagnosis, which generated four phenotypes. Several studies have suggested that these phenotypes could differ in their metabolic and endocrine characteristics and that they could vary in the same patient when analyzed throughout life. AIM: To determine if the initial classification of PCOS phenotypes is modified by different physiological conditions. MATERIAL AND METHODS: We performed a non-concurrent prospective analysis of 88 women with PCOS according to the Rotterdam criteria. The effect of physiological conditions such as changes in body weight, pregnancy and ageing more than five years on PCOS phenotype expression was analyzed. RESULTS: Twenty four percent of women became pregnant, 37% decreased and 24% increased their body weight during follow up. These conditions modified significantly the proportion of the different phenotypes (c2 = 32.2, p < 0.001). For instance, weight reduction was associated with a change to a better phenotype (p = 0.047) and even a normalization of the PCOS condition in 27% of the patients. On the other hand, an increase in body weight modifying body mass index in one unit, conferred an 8% probability of changing to a worst phenotype. CONCLUSIONS: Pregnancy and changes in body weight significantly modify PCOS phenotypes.

Clasificación de los fenotipos de síndrome de ovario poliquístico de acuerdo a los criterios de Rotterdam: ¿una condición estática o variable? / Effects of pregnancy and changes in body weight on polycystic ovary syndrome phenotypes according to the Rotterdam criteria

Background: Polycystic Ovary Syndrome (PCOS) is tightly associated with insulin resistance and obesity and characterized by hyperandrogenism, chronic oligo-anovulation and polycystic ovarian morphology when fully expressed. The 2003 Rotterdam consensus proposed that two or three of these features were necessary to make the diagnosis, which generated four phenotypes. Several studies have suggested that these phenotypes could differ in their metabolic and endocrine characteristics and that they could vary in the same patient when analyzed throughout life. Aim: To determine if the initial classification of PCOS phenotypes is modified by different physiological conditions. Material and Methods: We performed a non-concurrent prospective analysis of 88 women with PCOS according to the Rotterdam criteria. The effect of physiological conditions such as changes in body weight, pregnancy and ageing more than five years on PCOS phenotype expression was analyzed. Results: Twenty four percent of women became pregnant, 37% decreased and 24% increased their body weight during follow up. These conditions modified significantly the proportion of the different phenotypes (c2 = 32.2, p < 0.001). For instance, weight reduction was associated with a change to a better phenotype (p = 0.047) and even a normalization of the PCOS condition in 27% of the patients. On the other hand, an increase in body weight modifying body mass index in one unit, conferred an 8% probability of changing to a worst phenotype. Conclusions: Pregnancy and changes in body weight significantly modify PCOS phenotypes.

Metabolic profile of the different phenotypes of polycystic ovary syndrome in two Latin American populations.

OBJECTIVE: To evaluate the metabolic profile of Chilean and Argentinian women with polycystic ovary syndrome (PCOS) according to the Rotterdam criteria. DESIGN: Observational cross-sectional study. SETTING: Academic centers. PATIENT(S): Women with PCOS, aged 18-39 years: 220 Chilean (PCOSCh) and 206 Argentinian (PCOSAr). INTERVENTION(S): Physical examination, fasting blood samples for androgens, gonadotropins, metabolic parameters, and a transvaginal ultrasound. MAIN OUTCOME MEASURE(S): Comparative analysis of the metabolic profile in both populations divided into four phenotypes. RESULT(S): The distribution of the different phenotypes was different in both populations. PCOSCh women showed a higher body mass index and a higher percentage of metabolic syndrome in all phenotypes compared with the PCOSAr women. The PCOSAr women exhibited a statistically significantly higher diastolic blood pressure in phenotypes A, B, and C and a higher percentage of hypertension in phenotypes A and D compared with the PCOSCh women. CONCLUSION(S): The data show differences in the metabolic profile of both populations. PCOSCh women presented with greater metabolic alterations such as dysglycemia and dyslipidemia and a higher prevalence of metabolic syndrome, independent of the phenotype. The PCOSAr patients showed more elevated blood pressure. Ethnic diversity associated with environmental factors are fundamental elements in the analysis of the PCOS phenotypes.

Síndrome de ovario poliquístico y embarazo / Polycystic ovary syndrome and pregnancy

Background: Polycystic ovary syndrome (PCOS) is a common endocrine metabolic dysfunction closely associated with insulin resistance and obesity, which predisposes to pregnancy complications and prenatal programming of the offspring. The aim of this review is to report our experience in PCOS patients who became pregnant and were followed during the whole pregnancy. Firstly, we analyzed the effect of pregnancy on PCOS pathophysiology and secondly the role of PCOS in pregnancy outcomes. Regarding the firstpoint, during normal pregnancy a progressive insulin resistance, serum lipid changes and an increase in androgen levels is observed, which is exacerbated in the PCOS condition. This adverse intrauterine environment could have a prenatal programming effect with detrimental consequences for female or male fetuses. Regarding the second point, PCOS is associated with an increased risk for maternal complications such as gestational diabetes (GDM) and pregnancy-induced hypertension. Moreover, these adverse pregnancy outcomes are more frequently associated with an increase in low birth weight and high birth weight newborns. According to our clinical experience, PCOS patients who became pregnant and were not treated with metformin during the whole pregnancy, showed a higher prevalence of gestational diabetes and SGA newborns, which was improved with metformin treatment. In summary, pregnancy may constitute a period in which an abnormal condition is established or aggravated in the fetus of a PCOS mother. Moreover, PCOS enhanced adverse obstetric and neonatal outcomes.

CAG repeat polymorphism of androgen receptor gene and X-chromosome inactivation in daughters of women with polycystic ovary syndrome (PCOS): relationship with endocrine and metabolic parameters.

BACKGROUND: The polycystic ovary syndrome (PCOS) is a hyperandrogenic disorder that arise from a combination of genetic and environmental factors. AIM: To assess the role of the androgen receptor (AR) CAG repeat polymorphism in the metabolic and reproductive features in daughters of women with PCOS (PCOSd). METHODS: Sixty-seven PCOSd and 60 daughters of control women (Cd) were studied in early stages of sexual development. Sex steroids, glucose, insulin and lipids were determined. The AR CAG repeat sizes and X-chromosome inactivation (XCI) were analyzed. RESULTS: PCOSd and Cd had similar mean number of CAG repeats and XCI pattern. In PCOSd and Cd, methylation-weighted biallelic means CAGn (mwCAGn) was not associated with androgen levels. In infants and pubertal PCOSd, mwCAGn was associated with a low concentration of HDL-cholesterol. CONCLUSIONS: AR CAG repeat polymorphism appears to be unrelated with serum androgen levels. However, the short mwCAGn variant may have a possible impact on the lipid profile in PCOSd.

Relationship between anti-Müllerian hormone (AMH) and insulin levels during different tanner stages in daughters of women with polycystic ovary syndrome.

CONTEXT: We have previously described increased serum levels of anti-Müllerian hormone (AMH) and stimulated insulin in daughters of women with polycystic ovary syndrome (PCOS), suggesting that these girls may have an altered ovarian follicular development which may be modulated by insulin. However, the specific relationship between serum AMH and insulin levels during each Tanner stage of puberty in this cohort has not been established. OBJECTIVE: The aim of our study was to establish the relationship between AMH and poststimulated insulin serum concentrations during each stage of puberty in daughters of women with PCOS (PCOSd), compared to daughters of control women (Cd). DESIGN: We studied 135 PCOSd and 93 Cd classified according to their Tanner stage. Gonadotrophins, sex steroids, sex hormone-binding globulin (SHBG), and AMH were determined in a fasting sample. Ovarian volume was measured by pelvic ultrasound. In addition, in both groups we performed an oral glucose tolerance test with measurements of glucose and insulin. RESULTS: Anti-Müllerian hormone levels were significantly higher in PCOSd compared to Cd at all Tanner stages. Daughters of women with PCOS having AMH concentrations greater than 2 standard deviation (SD) above the mean AMH value for the Cd group showed decreased serum follicle-stimulating hormone (FSH) concentrations and increased stimulated levels of insulin during Tanner stages I, II, and III. CONCLUSIONS: Anti-Müllerian hormone levels are increased in PCOSd during all stages of puberty. We suggest that those PCOSd with the highest AMH levels probably represent a group of girls with more severe ovarian dysfunction and metabolic derangements.

[Polycystic ovary syndrome and pregnancy]. / Síndrome de ovario poliquístico y embarazo.

Polycystic ovary syndrome (PCOS) is a common endocrine metabolic dysfunction closely associated with insulin resistance and obesity, which predisposes to pregnancy complications and prenatal programming of the offspring. The aim of this review is to report our experience in PCOS patients who became pregnant and were followed during the whole pregnancy. Firstly, we analyzed the effect of pregnancy on PCOS pathophysiology and secondly the role of PCOS in pregnancy outcomes. Regarding the firstpoint, during normal pregnancy a progressive insulin resistance, serum lipid changes and an increase in androgen levels is observed, which is exacerbated in the PCOS condition. This adverse intrauterine environment could have a prenatal programming effect with detrimental consequences for female or male fetuses. Regarding the second point, PCOS is associated with an increased risk for maternal complications such as gestational diabetes (GDM) and pregnancy-induced hypertension. Moreover, these adverse pregnancy outcomes are more frequently associated with an increase in low birth weight and high birth weight newborns. According to our clinical experience, PCOS patients who became pregnant and were not treated with metformin during the whole pregnancy, showed a higher prevalence of gestational diabetes and SGA newborns, which was improved with metformin treatment. In summary, pregnancy may constitute a period in which an abnormal condition is established or aggravated in the fetus of a PCOS mother. Moreover, PCOS enhanced adverse obstetric and neonatal outcomes.

Improvement of hyperandrogenism and hyperinsulinemia during pregnancy in women with polycystic ovary syndrome: possible effect in the ovarian follicular mass of their daughters.

OBJECTIVE: To evaluate the ovarian function during early infancy in daughters of women with polycystic ovary syndrome (PCOS) treated with metformin throughout pregnancy (PCOSd+M), as a means to reduce androgen and insulin levels, compared with daughters of nontreated PCOS women (PCOSd-M) and daughters of women who belong to a healthy comparison group (HCd). DESIGN: Descriptive and analytic study. SETTING: Unit of endocrinology and reproductive medicine. PATIENT(S): Fifteen PCOSd+M, 23 PCOSd-M, and 35 HCd were studied at 2-3 months of age. INTERVENTION(S): A GnRH analogue test was performed with determinations of gonadotropins, sex steroids, SHBG, and anti-Müllerian hormone (AMH). MAIN OUTCOME MEASURE(S): Differences in AMH levels between PCOSd+M, PCOSd-M and HCd. RESULT(S): AMH and peak E(2) concentrations were significantly higher in PCOSd-M compared with HCd, whereas PCOSd+M exhibited AMH concentrations and peak E(2) levels similar to those observed in HCd. CONCLUSION(S): The improvement of the altered endocrine-metabolic environment of PCOS mothers reduces AMH levels in their daughters, which might reflect a decrease in their follicular mass.

Caracterización del síndrome de ovarios poliquísticos desde el término de la edad reproductiva hasta la menopausia / Ovarian function during late reproductive age and early menopausal transition in women with polycystic ovary syndrome

The higher life expectancy and prevalence of obesity among women has increased the prevalence of diseases associated to metabolic syndrome such as polycystic ovary disease and cardiovascular diseases. Polycystic ovary disease is common among women of reproductive age and the main cause of hyperandrogenism. Multiple growing follicles and increased ovarian stroma are observed. Hyperinsulinemia, commonly associated with the syndrome, stimulates follicle development, ovarian volume and cardiovascular risk. After the age of 35 years, the late reproductive ages ensues in healthy women with a reduction in the number of ovarian follicles. This is accentuated after the age of 40, when menopausal transition starts. Women with polycystic ovary syndrome could experience a delay in the onset of menopause due to their elevated androgen and insulin levels and their increased follicular mass. This is a review about the endocrine and metabolic changes experienced by women with polycystic ovary syndrome from the end of their reproductive life to their menopause. The mechanisms that differentiate these women from their healthy counterparts are discussed.

Metabolic and reproductive features before and during puberty in daughters of women with polycystic ovary syndrome.

CONTEXT: A significant proportion of the first-degree female relatives of women with polycystic ovary syndrome (PCOS) may be at risk for developing PCOS. However, it is not known at which stage of pubertal development the hormonal and metabolic abnormalities ensue in PCOS. OBJECTIVE: The aim of the study was to assess the reproductive and metabolic profiles of daughters of women with PCOS (PCOSd) during the peripubertal period, a stage during which the gonadal axis is activated and PCOS may become clinically manifest. DESIGN: Ninety-nine PCOSd [30 prepubertal and 69 pubertal (Tanner II-V)] and 84 daughters of control women (Cd) (20 prepubertal and 64 pubertal) were studied. An oral glucose tolerance test, a GnRH agonist test (leuprolide acetate, 10 microg/kg sc), and a transabdominal ultrasound were performed. Gonadotropins, sex steroids, SHBG, glucose, insulin, and lipids were determined. RESULTS: Both groups had similar chronological ages and body mass index sd scores according to Tanner stage distribution. Ovarian volume and 2-h insulin were significantly higher in PCOSd compared to Cd at all Tanner stages. In Tanner stages IV and V, basal testosterone and poststimulated LH, testosterone, and 17-hydroxyprogesterone concentrations were significantly higher in PCOSd compared to Cd. CONCLUSIONS: Hyperinsulinemia and an increased ovarian volume are present in PCOSd before the onset of puberty and persist during pubertal development. The biochemical abnormalities of PCOS appear during late puberty. Considering the early onset and the nature of the alterations, PCOSd constitute a high-risk group for metabolic and reproductive derangements.

Actualizaciones sobre el manejo del loxoscelismo / Update on loxoscelilsm management

Loxoscelismo es el cuadro tóxico provocado por el veneno que arañas del género Loxosceles inyectan en el momento de la mordedura, siendo la especie laeta su única representante en Chile. El cuadro clínico puede presentarse en dos formas: loxoscelismo cutáneo y cutáneo-visceral, cada una de ellas con características distintivas. El objetivo del trabajo es actualizar la información existente sobre el manejo de este cuadro para lo cual se revisa la literatura chilena e internacional publicada (Medline, Cochrane y otras bases de dato). Se puede concluir que la alta frecuencia de consultas debido a mordedura de arañas obliga al médico a saber prevenirlas, diagnosticarlas y tratarlas. Aún no existen estudios que demuestren la efectividad de los tratamientos usados en nuestros días. Se sugiere que sería importante establecer un protocolo de manejo en nuestro hospital.