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.

Hypothalamic transcriptional expression of the kisspeptin system and sex steroid receptors differs among polycystic ovary syndrome rat models with different endocrine phenotypes

OBJECTIVES: Polycystic ovary syndrome is a heterogeneous endocrine disorder that affects reproductive-age women. The mechanisms underlying the endocrine heterogeneity and neuroendocrinology of polycystic ovary syndrome are still unclear. In this study, we investigated the expression of the kisspeptin system and gonadotropin-releasing hormone pulse regulators in the hypothalamus as well as factors related to luteinizing hormone secretion in the pituitary of polycystic ovary syndrome rat models induced by testosterone or estradiol. METHODS: A single injection of testosterone propionate (1.25 mg) (n=10) or estradiol benzoate (0.5 mg) (n=10) was administered to female rats at 2 days of age to induce experimental polycystic ovary syndrome. Controls were injected with a vehicle (n=10). Animals were euthanized at 90-94 days of age, and the hypothalamus and pituitary gland were used for gene expression analysis. RESULTS: Rats exposed to testosterone exhibited increased transcriptional expression of the androgen receptor and estrogen receptor-β and reduced expression of kisspeptin in the hypothalamus. However, rats exposed to estradiol did not show any significant changes in hormone levels relative to controls but exhibited hypothalamic downregulation of kisspeptin, tachykinin 3 and estrogen receptor-α genes and upregulation of the gene that encodes the kisspeptin receptor. CONCLUSIONS: Testosterone- and estradiol-exposed rats with different endocrine phenotypes showed differential transcriptional expression of members of the kisspeptin system and sex steroid receptors in the hypothalamus. These differences might account for the different endocrine phenotypes found in testosterone- and estradiol-induced polycystic ovary syndrome rats.

Síndrome de ovario poliquístico (SOP) y embarazo: Experiencia clínica / Polycystic ovary syndrome and pregnancy: Clinical experience

Background: Polycystic ovary syndrome (PCOS) is an endocrine metabolic dysfunction closely associated with insulin resistance and obesity, which predisposes to pregnancy complications. Aim: To report a prospective clinical experience in PCOS patients who became pregnant after diet, exercise and metformin treatment intervention, and were followed up during the whole pregnancy. Patients and Methods: Seventy pregnant PCOS (PPCOS) women and forty normal pregnant (NP) women of similar age and with singleton pregnancies were included in the study. During gestational ages 10-16 and 22-28 weeks, a 2h, 75 g oral glucose tolerance test (OGTT) was performed with measurement of glucose and insulin in each sample. Results: No differences were found in duration of gestation, weight gain during pregnancy, or systolic and diastolic blood pressure between PPCOS and NP women. There were significant differences in body mass index (BMI) at the initiation and in the third trimester of pregnancy between both groups. The incidence of gestational diabetes was significantly higher (p <0.01) in the PCOS group (35.2 percent) compared to the control group (5.0 percent). The prevalence of small for gestational age (SGA) infants tended to be higher (p =0.09) in the PCOS group. During pregnancy, 2h glucose and insulin were significantly higher in PPCOS than in NP women. Conclusions: PCOS mothers showed a higher prevalence of gestational diabetes and SGA newborns, which cannot be attributed to the weight gain during pregnancy, and seems to be more related to the BMI at the initiation of pregnancy, and to the PCOS condition of the mothe.

La exposición prenatal a andrógenos como factor de reprogramación fetal / Prenatal exposure to androgens as a factor of fetal programming

Both epidemiological and clinical evidence suggest a relationship between the prenatal environment and the risk of developing diseases during adulthood. The first observations about this relationship showed that prenatal growth retardation or stress conditions during fetal life were associated to cardiovascular, metabolic and other diseases in later life. However, not only those conditions may have lasting effects after birth. Growing evidence suggests that prenatal exposure to steroids (either of fetal or maternal origin) could be another source of prenatal programming with detrimental consequences during adulthood. We have recently demonstrated that pregnant women with polycystic ovary syndrome exhibit elevated androgen levels compared to normal pregnant women, which could provide an androgen excess for both female or male fetuses. We have further tested this hypothesis in an animal model of prenatal androgenization, finding that females born from androgenized mothers have a low birth weight and high insulin resistance, that starts at an early age. On the other hand, males have low testosterone and LH secretion in response to a GnRH analogue test compared to control males and alterations in seminal parameters. We therefore propose that our efforts should be directed to modify the hyperandrogenic intrauterine environment to reduce the potential development of reproductive and metabolic diseases during adulthood.

Síndrome de ovario poliquístico, obesidad e hiperinsulinismo: un camino a la diabetes / Polycystic ovary syndrome POS, obesity and hyperinsulinism: a course to diabetes

El síndrome de ovario poliquístico(SOP) es una disfunción endocrinometabólica heterogénea de alta prevalencia, con una probable base genética, que compromete la función reproductiva de la mujer joven y que se encuentra en estrecha asociación a la insulinorresistencia (IR), Dentro de su compleja fisiopatología destacan la hipersecreción de LH e insulina, las cuales agravan una alteración preexistente de la biosíntesis esteroidal. La presencia de IR predispone a estas pacientes a desarrollar complicaciones cardiovasculares y metabólicas, las que suelen ser precoces. Por otro lado, la incidencia de patologías metabólicas asociadas a IR es mayor en los familiares de pacientes SOP que en los de mujeres normales, de ahí que el tratamiento de este síndrome no sólo debe ser sintomático, sino fundamentalmente preventivo. Asimismo, el SOP debería ser considerado un marcador de una patología familiar, un camino a la diabetes y un problema de salud pública

Insulinorresistencia: generalidades e implicancias clínicas / Insulin resistance generalties and clinical approach

La insulinorresistencia, es la base fisiopatológica de múltiples enfermedades de alta prevalencia, entre las que se destacan: la obesidad androide, la intolerancia a la glucosa, la diabetes mellitus, la hipertensión arterial y la dislipidemia. Además, se presenta en otras situaciones patológicas frecuentes, entre otras, diabetes gestacional, ovario poliquístico y en sujetos pequeños para la edad gestacional. Finalmente, está presente en una serie de condiciones fisiológicas y patológicas poco frecuentes o muy excepcionales, ya sea de origen genético, congénitas o adquiridas. Quizás más que por su prevalencia, el principal problema reside en, que esta condición puede permanecer desconocida y el daño metabólico puede ocurrir mucho antes que un exámen fortuito o el cuadro florido de una diabetes 2 nos lleve finalmente a su diagnóstico. El propósito de esta revisión es dar una orientación diagnóstica práctica de este síndrome tanto desde el punto de vista clínico como de las metodologías actualmente en uso

Leptina y sistema reproductivo / Leptin and the reproductive system

La leptina es una hormona proteica recientemente descubierta, la cual es producida por los adipocitos. Esta actúa regulando el apetito, el peso corporal y la termogénesis. Su posible rol como modulador en el eje reproductivo se ha inferido de una cepa de ratas carentes de leptina, que se caracterizan por ser obesas, diabéticas e infértiles y en las que el administrar esta hormona se producen cambios como disminución del apetito, aumento del gasto energético y recuperación de la fertilidad. Estos fenómenos han motivado una gran cantidad de estudios para establecer el rol la leptina en el sistema reproductivo. Se revisa la literatura existente sobre leptina y su acción sobre los cambios de peso corporal, pubertad, sistema nervioso central y periférico, ovarios y embarazo