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.

Metformin improves polycystic ovary syndrome and activates female germline stem cells in mice / 生理学报

Polycystic ovary syndrome (PCOS) is a common disease caused by complex endocrine and metabolic abnormalities in women of childbearing age. Metformin is the most widely used oral hypoglycemic drug in clinic. In recent years, metformin has been used in the treatment of PCOS, but its mechanism is not clear. In this study, we aimed to investigate the effect of metformin on PCOS and its mechanism through PCOS mouse model. Female C57BL/6J mice aged 4-5 weeks were intragastrically given letrozole (1 mg/kg daily) combined with a high-fat diet (HFD) for 21 days to establish the PCOS model. After modeling, metformin (200 mg/kg daily) was intragastrically administered. One month later, the body weight and oral glucose tolerance test (OGTT) were measured. Hematoxylin eosin (H&E) staining was used to detect the pathological changes of ovary. The serum levels of anti-Mullerian hormone (AMH), follicle-stimulating hormone (FSH), luteinizing hormone (LH), E2 and testosterone (T) were measured by ELISA. The expression of DDX4/MVH was detected by immunohistochemistry. DDX4/MVH and PCNA were co-labeled by immunofluorescence. The protein levels of DDX4/MVH, PCNA, cyclin D2, AMPK and mTOR were detected by Western blot. The results showed that after metformin treatment, the body weights of PCOS mice were gradually returned to normal, glucose tolerance was significantly improved, serum E2 levels were increased, while AMH, LH, T levels and LH/FSH ratio were decreased. Ovarian polycystic lesions were reduced with reduced atresia follicles. Furthermore, the number of proliferative female germline stem cells (FGSCs) and levels of proliferation related proteins (PCNA, cyclin D2) were significantly increased, and the p-mTOR and p-AMPK levels were markedly up-regulated. These results suggest that metformin treatment not only improves hyperandrogenemia, glucose intolerance and polycystic ovarian lesions in PCOS, but also activates the function of FGSCs. The underlying mechanism may be related to the phosphorylation of AMPK and mTOR. These findings provide new evidence to use metformin in the treatment of PCOS and follicular development disorder.

Bushen Huatan recipe for treatment of polycystic ovary syndrome: therapeutic mechanism based on network pharmacology and molecular docking / 南方医科大学学报

OBJECTIVE@#To explore the pharmacological mechanism of Bushen Huatan (BSHT) recipe in the treatment of polycystic ovary syndrome (PCOS).@*METHODS@#The active ingredients in the component drugs of the recipe were screened through TCMSP, and their potential targets were predicted by PubChem and Swiss target prediction. Genecards and OMIM were used to screen the therapeutic targets in the treatment of PCOS. The drug targets and disease targets were corrected using Uniprot, and the intersection targets were obtained. The protein-protein interaction (PPI) network was constructed using STRING, and the intersection targets were analyzed with CytoNCA to screen the core targets. DAVID was used for GO enrichment analysis and KEGG pathway enrichment analysis, and the core components and core targets were verified using AutoDock. Animal experiment was performed to verify the results using a female C57BL/6J mouse model of PCOS, treated daily with 1 mg/kg BSHT recipe granule for 35 days, and the ovarian expressions of the core targets and pathways were detected using Western blotting.@*RESULTS@#We identified a total of 125 potential active ingredients from the 14 component drugs in the recipe, 990 drug targets, 4759 PCOS targets and 434 intersection targets. The core active ingredients of the recipe included β -Sitosterol, kaempferol, and quercetin, whose core targets included PIK3CA, PIK3R1, APP, AKT1, and MAPK1. GO enrichment analysis highlighted such processes as drug reaction, negative regulation of apoptosis, and positive regulation of transcription from RNA polymerase Ⅱ promoter. The enriched KEGG pathways included primarily the cancer pathway and PI3K-Akt signaling pathway. Molecular docking showed that the core active ingredients had strong binding ability with the core targets. In the animal experiment, BSHT recipe was shown to improve the symptoms, down-regulate the expressions of PI3K and Akt proteins and up-regulate MAPK1 expression in the ovary of mice with PCOS.@*CONCLUSION@#The therapeutic mechanism of BSHT recipe for PCOS involves multiple active ingredients, multiple therapeutic targets and multiple pathways.

Atualizações na terapêutica farmacológica para infertilidade na mulher diagnosticada com síndrome de ovários policísticos: revisão de literatura / Updates on pharmacological treatments for infertility in women diagnosed with polycystic ovary syndrome: a literature review

Objetivo: Abordar atualizações referentes à terapia medicamentosa para indução da ovulação nas mulheres diagnosticadas com síndrome dos ovários policísticos (SOP). Métodos: Revisão de literatura por meio de levantamento bibliográfico do período de 1975 a 2021, nas bases eletrônicas PubMed, SciELO e MedLine, complementado pela Diretriz Internacional Baseada em Evidências para a Avaliação e Manejo da SOP de 2018 e pelo manual da Febrasgo para SOP. Sete descritores que atendessem à finalidade da pesquisa foram utilizados. Resultados: A literatura aponta atualmente algumas drogas como opção na terapêutica para a indução de ovulação, como metformina, letrozol e citrato de clomifeno, evidenciando que o uso de letrozol isolado e em associação com a metformina apresentaram melhores taxas de ovulação, 71,5% e 75,4%, respectivamente. Conclusão: O uso do letrozol isolado ou combinado com a metformina apresentou os melhores resultados nas taxas de gravidez e ovulação, todavia o tratamento para indução ovulatória deve ser individualizado.(AU)

Objective: To address updates of medicinal therapy for ovulation induction in women diagnosed with polycystic ovary syndrome (PCOS). Methods: Reviewing Literature through a bibliographic survey from 1975 to 2021, on the electronic databases PubMed, SciELO and MedLine, complemented by the International Evidence-Based Guideline for the Evaluation and Management of PCOS 2018 and the Febrasgo guide for PCOS. Seven descriptors that matched to the purpose of the research were applied. Results: Some drugs are currently indicated in the literature as an option for ovulation induction therapy, such as: metformin, letrozole and clomiphene citrate, showing that the use of letrozole alone and in association with metformin had better ovulation rates, 71.5% and 75.4%, respectively. Conclusion: The use of letrozole alone or combined with metformin showed the best results in pregnancy and ovulation rates, however, treatment for ovulatory induction must be individualized.(AU)

Short-term combined treatment with exenatide and metformin for overweight/obese women with polycystic ovary syndrome / 中华医学杂志(英文版)

BACKGROUND@#Obesity and insulin resistance (IR) are common features of polycystic ovary syndrome (PCOS). Metformin (MET) increases insulin sensitivity, but it is associated with unsatisfactory weight loss. The glucagon-like peptide-1 receptor agonist exenatide has been shown to reduce weight and IR in patients with diabetes. This study aimed to explore the therapeutic effects of exenatide once-weekly (QW) combined with MET on body weight, as well as metabolic and endocrinological parameters in overweight/obese women with PCOS.@*METHODS@#Fifty overweight/obese women with PCOS diagnosed via the Rotterdam criteria were randomized to one of two treatment groups: MET (500 mg three times a day [TID]) or combination treatment (COM) (MET 500 mg TID, exenatide 2 mg QW) for 12 weeks. The primary outcomes were anthropometric changes associated with obesity, and the secondary outcomes included changes in reproductive hormone levels, glucose and lipid metabolism, and C-reactive protein.@*RESULTS@#Forty (80%) patients completed the study. COM therapy was superior to MET monotherapy in reducing weight (P = 0.045), body mass index (BMI) (P = 0.041), and waist circumference (P = 0.023). Patients in the COM group on an average lost 3.8 ± 2.4 kg compared with 2.1 ± 3.0 kg in the MET group. In the COM group, BMI and waist circumference decreased by 1.4 ± 0.87 kg/m2 and 4.63 ± 4.42 cm compared with 0.77 ± 1.17 kg/m2 and 1.72 ± 3.07 cm in the MET group, respectively. Moreover, levels of fasting glucose, oral glucose tolerance test (OGTT) 2-h glucose, and OGTT 2-h insulin were significantly lower with COM therapy than with MET (P < 0.050). Mild and moderate gastrointestinal reactions were the most common adverse events in both groups.@*CONCLUSIONS@#COM therapy was more effective than MET alone in reducing body weight, BMI, and waist circumference, and improving insulin sensitivity in overweight/obese women with PCOS, with acceptable short-term side effects.@*TRIAL REGISTRATION@#ClinicalTrials.gov, NCT04029272. https://clinicaltrials.gov/ct2/show/NCT04029272.

Therapeutic effects of dimethyldiguanide combined with clomifene citrate in the treatment of polycystic ovary syndrome

SUMMARY OBJECTIVE In view of the high incidence of polycystic ovary syndrome (PCOS) and the unsatisfactory therapeutic effects of dimethyldiguanide or clomifene citrate alone, our study aimed to investigate the therapeutic effects of dimethyldiguanide combined with clomifene citrate in the treatment of PCOS. METHODS A total of 79 patients with POCS and 35 healthy females were included, and endometrial biopsies were obtained. The sterol regulatory element-binding protein-1 (SREBP1) expression in endometrial tissues was detected by qRT-PCR. POC patients were randomly divided into group A (n=40) and group B (n=39). Patients in group A were treated with dimethyldiguanide combined with clomifene citrate, while patients in group B were treated with clomifene citrate alone. The number of mature follicles and cervical mucus score, follicular development rate and single follicle ovulation rate, cycle pregnancy rate, early miscarriage rate, ovulation rate, endometrial thickness, positive rate of three lines sign, follicle stimulating hormone level and luteinizing hormone level were compared between the two groups. RESULTS The expression level of SREBP1 was higher in PCOS patients than that in the healthy control. SREBP1 expression was inhibited after treatment, while the inhibitory effects of combined treatment were stronger than those of clomifene citrate alone. Compared with clomifene citrate alone, the combined treatment improved cervical mucus score, follicle development rate, single follicle ovulation rate, endometrial thickness, positive rate of three lines sign, and follicle-stimulating hormone level. CONCLUSION The therapeutic effect of combined treatment is better than clomifene citrate alone in the treatment of PCOS.

RESUMO OBJETIVO Tendo em vista a alta incidência de síndrome dos ovários policísticos (SOP) e os efeitos terapêuticos insatisfatórios da dimetildiguanida ou do citrato de clomifeno isoladamente, nosso estudo teve como objetivo investigar os efeitos terapêuticos da dimetildiguanida associada ao citrato de clomifeno no tratamento da SOP. MÉTODOS Um total de 79 pacientes com POCS e 35 mulheres saudáveis foram incluídos, e biópsias endometriais foram obtidas. A expressão da proteína de ligação do elemento regulador de esterol-1 (SREBP1) nos tecidos endometriais foi detectada por qRT-PCR. Pacientes POC foram divididos aleatoriamente em grupo A (n=40) e grupo B (n=39). Os pacientes do grupo A foram tratados com dimetildiguanida combinada com citrato de clomifeno, enquanto os pacientes do grupo B foram tratados apenas com citrato de clomifeno. O número de folículos maduros e muco cervical, taxa de desenvolvimento folicular e taxa de ovulação, taxa de gravidez, abortamento precoce, taxa de ovulação, espessura endometrial, taxa positiva de três linhas, nível de hormônio folículo estimulante e nível de hormônio luteinizante foram comparados entre os dois grupos. RESULTADOS O nível de expressão do SREBP1 foi maior nos pacientes com SOP do que no controle normal. A expressão de SREBP1 foi inibida após o tratamento, enquanto os efeitos inibidores do tratamento combinado foram mais fortes do que os do citrato de clomifeno isoladamente. Comparado com o citrato de clomifeno sozinho, o tratamento combinado melhorou significativamente a pontuação do muco cervical, a taxa de desenvolvimento folicular, a taxa de ovulação do folículo único, a espessura endometrial, a taxa positiva de três linhas de sinal e o nível de hormônio folículo estimulante. CONCLUSÃO O efeito terapêutico do tratamento combinado é melhor do que o citrato de clomifeno isolado no tratamento da SOP.

Metformina e citrato de clomifeno no tratamento de fertilidade na síndrome dos ovários policísticos / Metformin and clomiphene citrate in polycystic ovary syndrome's treatment

A síndrome dos ovários policísticos (SOP) é uma complexa desordem endócrina caracterizada por distúrbios reprodutivos e metabólicos, sendo a causa mais comum de infertilidade ovariana. A prevalência é entre 5 e 10% em mulheres na idade reprodutiva. Sua etiologia permanece obscura e a variabilidade de expressão fenotípica continua a desafiar os cuidados clínicos e pesquisas sobre a heterogeneidade desta condição. Embora mudanças no estilo de vida bem como o uso de citrato de clomifeno (CC) serem o padrão para o tratamento da infertilidade nestas pacientes, o uso da metformina tem se destacado como tratamento para esse fim ante sua eficácia. Partindo deste princípio, esta revisão tem por objetivo avaliar a eficácia da metformina em melhorar as taxas de ovulação e de gravidez clínica, seja como tratamento isolado ou combinado ao CC.(AU)

The polycystic ovary syndrome (PCOS) is a complex endocrine disease characterized by reproductive and metabolic disorders. It is the most common cause of ovarian infertility and has a prevalence of 5-10% in reproductive age women. Its etiology remains unclear, and the variability of phenotypic expression continues to yield clinical care and research on the heterogeneity of this challenging condition. Although life style changes as well as the use of clomiphene citrate (CC) is a standard treatment of infertility in these patients; metformin use has been highlighted in recent years as a treatment for this purpose due its effectiveness in treating PCOS. Based on this principle, this review aims to assess the metformin effectiveness in improving ovulation rates and clinical pregnancy, either alone or in combination as the CC treatment.(AU)

Síndrome de ovario poliquístico / Polycystic ovary syndrome

El síndrome de ovario poliquísticos (SOP) representa una de las endocrinopatías más frecuentes en la mujer y es la principal causa de hiperandrogenismo (HA). Se trata de un trastorno complejo, multifactorial, poligénico con influencias ambientales. Aunque se han propuestos diferentes criterios para su diagnóstico, se prefiere el uso del más abarcativo (Criterio de Rotterdam) con la presencia de 2 de 3 de los siguientes: 1) HA clínico o bioquímico, 2) oligoanovulación crónica (OA), 3) poliquistosis ovárica por ecografía, excluyendo otras etiologías. Es frecuente su asociación con comorbilidades metabólicas (obesidad, diabetes 2, dislipidemia, apnea del sueño, etc.) y trastornos reproductivos (hiperplasia endometrial e infertilidad), sobre todo en los fenotipos clásicos, con HA y OA. El tratamiento estará orientado a las características clínicas de cada paciente y al deseo reproductivo. La pérdida de peso en aquellas con sobrepeso u obesidad o ambos factores puede restaurar los ciclos menstruales y disminuir el riesgo metabólico y representa la primera línea de tratamiento. Los anticonceptivos orales (ACO) son el tratamiento farmacológico de elección ya que atenúan las manifestaciones de HA y ofrecen protección endometrial. En las pacientes con oligoanovulación que buscan embarazo, el citrato de clomifeno es el tratamiento aconsejado en primera instancia. La metformina podría usarse en aquellas con intolerancia a la glucosa o diabetes 2 y también como segunda línea de tratamiento para restaurar los ciclos e inducir la ovulación. (AU)

Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in women, the main cause of hyperandrogenism (HA). It is a complex, multifactorial polygenic disorder with environmental influences. Although there have been proposed different criteria for diagnosis, using the most comprehensive (Criteria Rotterdam) with the presence of 2 of 3 of the following is preferred: 1) HA clinical or biochemical, 2) oligo-anovulation chronic (OA), 3) polycystic ovaries by ultrasound, excluding other etiologies. It is frequently associated with metabolic comorbidities (obesity, type 2 diabetes, dyslipidemia, sleep apnea, etc.) and reproductive disorders (endometrial hyperplasia and infertility), especially in the classical phenotypes, with HA and OA. The treatment will be oriented to the clinical characteristics of each patient and reproductive desire. Weight loss in those who are overweight and / or obesity can restore menstrual cycles and decrease metabolic risk and represents the first line of treatment. Oral contraceptives (OC) are the pharmacological treatment of choice as it attenuates the manifestations of HA and offer endometrial protection. In patients seeking pregnancy with oligo-anovulation, clomiphene citrate would be used at first instance. Metformin may be used in those with impaired glucose tolerance or type 2 diabetes and also as a second-line treatment to restore cycles and induce ovulation. (AU)

Evaluation of fenugreek [Trigonella foenum-graceum L.], effects seeds extract on insulin resistance in women with polycystic ovarian syndrome

PCOS [Polycystic Ovarian Syndrome] is associated with insulin resistance, obesity and disorders of lipid metabolism as well as infertility. Fenugreek seeds extract is successfully used in lowering blood glucose. Metformin has also the same effect but in a different way. The aim of this study was the assessment of fenugreek effects on insulin resistance in women with PCOS. This was a prospective randomized, double-blind, placebo-controlled trial. The study was conducted at the Montaserieh Hospital in Mashhad University of Medical Sciences, Mashhad, Khorasan Razavi Province, Iran. The patient population included 58 oligo-anovulatory PCOS women with typical ovaries. Women were randomly allocated to receive hydroalcoholic extract of fenugreek seeds in capsules with metformin [n = 30] or placebo capsules with metformin [n = 28] and were assessed before and every 4 weeks within a treatment period of 8 weeks. Menstrual disturbance and metabolic parameters [markers of insulin resistance and hormonal parameters] were measured. Insulin resistance based on HOMA-IR [homeostasis model assessment for insulin resistance] model was not significantly different between two groups. Ultrasound scans were performed before and at the end of 8 weeks treatment with significant decrease in PAO [polycystic appearing ovaries] in group 1 [p = 0/01]. Adjuvant therapy to the fenugreek seeds extract [with metformin] in PCOS women improved the sonographic results and menstrual cyclicity

Can sex-hormone binding globulin considered as a predictor of response to pharmacological treatment in women with polycystic ovary syndrome?

This study aims to evaluate the sex hormone binding globulin [SHBG] level as a predictor of response to pharmacological treatment in women with polycystic ovary syndrome [PCOS]. This study was conducted in 2009-2012 in Isfahan, Iran. Anovulatory women with a diagnosis of PCOS were studied. Metformin was started at 500 mg three times a day. If no ovulation occurred, Clomiphene citrate was added. The study comprised 273 infertile women with PCOS completed the study, 75 [28%] of them became pregnant 6 months after treatment [7.36% with metformin and 20.14% with metformin and clomiphene citrate]. Patients who responded to metformin treatment had significantly lower mean SHBG levels compared to those who did not [0.88+0.32vs. 0.2642+0.44 nmol/L, respectively, P<0.0001]. The area under the ROC curve [AUC] for prediction the response to treatment was 0.85. The baseline level of 27 was the most appropriate cut of point HSBG for the prediction of conception. HSBG had a sensitivity of 88%, and specificity of 73.6%. It had a false positive level of 26.4% and false negative level of 12%. Its positive predictive value was 56.4% and its negative predictive value was 94%. The chance of conception increased for reducing a unit of fpg [OR = 0.69; 95% CI = 0.54-0.86; P = .002], as well as reducing of every unit of HSBG [OR = 0.47; 95% CI = 0.39-0.56; P <0.001], and for reducing each unit of insulin in [OR = 0.082; 95% CI = 1.021-0.33; P <0.001]. HSBG test is suggested as an appropriate test for predicting pregnancy achievement of PCOs women after pharmacological treatment

Comparison of highly purified urinary versus recombinant FSH: effect on ART outcomes in polycystic ovary syndrome

Polycystic ovary syndrome [PCOS] is a common cause of ovulatory disorders and infertility with high LH to FSH ratio. In order to prevent further increase of LH and follicle atresia, different regimens for ovulation induction have been recommended using FSH alone. This study was performed in PCOS patients to compare ART outcomes in cycles induced by FSH alone, using either recombinant or urinary products. In a randomized trial, from 623 patients who underwent down regulation with GnRH analogue in a long protocol, 160 PCOS patients were randomly divided into two groups of 80. Group A received 150 IU/d recombinant FSH [Gonal-F] and group B 150 IU/d urinary FSH [Fostimon]. 33 cases [41.2%] in group A and 36 [45%] in group B achieved clinical pregnancy, which was not significantly different [p=0.67]. Total number of oocytes retrieved [13.03 +/- 5.56 vs. 14.17 +/- 4.89, p=0.17], quality and number of embryos [7.42 +/- 3.35 vs. 7.63 +/- 3.28, p=0.68] and OHSS rate were similar in group A compared to group B. Endometrial thickness which was 9.66 +/- 1.67 mm in group A and 10.36 +/- 1.35 mm in group B, showed a significant difference [p=0.004]. It seems that in PCOS patients, both pure FSH products used for controlled ovarian hyperstimulation have similar effects on ART outcome and can be used according to availability and patient acceptance without significant difference

Efecto de un anticonceptivo oral con drospirenona/etinilestradiol (3 mg - 30 mg) sobre el hiperandrogenismo clínico y bioquímico en pacientes con síndrome de ovario poliquístico / Effect of an oral contraceptive containing drospirenone / ethinyl estradiol (3 mg - 30 mg) on the clinical and biochemical hyperandrogenism in patients with polycystic ovary syndrome

El síndrome de ovario poliquístico es un desorden heterogéneo de etiología incierta, que cual afecta entre el 6% y 10% de las mujeres en edad reproductiva. Una de las opciones terapéuticas especificas es el uso de los anticonceptivos orales, con la progestina, drospirerona, la cual, es un análogo de la espironolactona que posee actividad antimineralcorticoides y antiandrogénica. El objetivo de este estudio fue determinar el efecto del anticonceptivo oral combinado (EE: 30 MG y DRP: 3 mg) en el perfil bioquímico y clínico en una población de mujeres venezolanas con síndrome de ovario poliquístico. De las 20 pacientes incluidas en el estudio, 18 completaron satisfactoriamente el estudio, con una buena tolerancia al tratamiento. Se observó una disminución del IMC de 23,94 en condición basal a 23,73 kg/m². Los niveles de andrógenos se encontraron disminuidos significativamente en comparación a la basal; testosterona total cayó de 1,4 ng/mL a 0,67 ng/mL; Testosterona libre bajo de 3 pg/mL a 1,38 pg/mL; DHEAS disminuyó de 1,65 µg/mL a 1,08 µg/mL y androstenediona de 2,50 ng/mL a 1,55 ng/mL. En conclusión nuestros resultados reportan que el uso de un anticonceptivo oral que contiene 30 mg de EE y 3 mg de progestina, drospirerona en una población de mujeres venezolanas con síndrome de ovario poliquístico condujo a una disminución de los niveles de andrógenos al mismo tiempo que se evidenció un incremento de la SHBG, así como una reducción no significativa del peso corporal de este grupo de pacientes y una mejoría clínica del hirsutismo.

Policystic ovarian syndrome is a heterogeneous disorder wich etiology remained uncertain and affects 6%-10% of reproductive age women. Most recommended therapy is oral contraceptives with progestins. Drospirenone is an espironolactone analogue exhibits a partial antiandrogenic action and has predominant anti-mineralocorticoid properties. This is a prospective trial to determine efficacy of a drospirenone-containing combined oral contraceptives in venezuelan women with polycystic ovary-syndrome. Twenty women were conducted into this trial, although 18 were treated. With treatment, BMI fell by 0,21 kg/m(2) in the study group. During therapy, the levels of testosterone, free testosterone, Delta (4)-androstenedione, and androstenedione decreased significantly, whereas sex hormone-binding globulin increased significantly. Treatment of women with polycystic ovary-syndrome with drospironene containing combined oral contraceptives formulations is effective in decreasing hirsutism, androgen levels and BMI.

Metformin-letrozole in comparison with metforminclomiphene citrate in clomiphene-resistance PCOS patients undergoing IUI

Polycystic ovary syndrome [PCOS] is associated with approximately 75% of women who suffer from infertility due to anovulation. Additionally, around 20-25% of anovulatory women with PCOS do not respond at all to clomiphene citrate and are considered to be "clomiphene-resistant". Aromatase inhibitors have been suggested as an alternative treatment to clomiphene as the discrepancy between ovulation and pregnancy rates with clomiphene citrate has been attributed to its anti-estrogenic action and estrogen receptor depletion. The aim of this study is to compare results of Metformin-letrozole with Metformin-clomiphene citrate in clomiphene resistance PCOS patients undergoing IUI. In this single blind randomized trial, ovarian cycles were studied in 100 clomiphene- resistant patients with PCOS. The inclusion criteria were patients who received 150mg clomiphene citrate daily for 3 cycles and failed to become pregnant. The patients were matched for their age, body mass index [BMI], and infertility period. They were randomly allocated to a metformin-letrozole group [n=50] and a metformin-clomiphene citrate group [n=50]. Chemical and clinical pregnancies were assessed after IUI. Abortion rates were determined in both groups. Regarding pregnancy rate, there was no significant difference between the two groups. One miscarriage [2%] occurred in the metformin-clomiphene citrate group, whereas none was seen in the metformin-letrozole group. There is no significant difference in pregnancy rate between clomiphene citrate and letrozole groups although it has been 2% in the former and 5% in the latter

Uso de la metformina en el tratamiento de pacientes infértiles con síndrome de ovarios poliquísticos / Use of metformin in the treatment of infertile patients with polycystic ovary syndrome

Determinar el efecto de la terapia con metformina en pacientes infértiles con síndrome de ovarios poliquísticos. Estudio clínico, prospectivo y descriptivo. Incluyó pacientes con diagnóstico de síndrome de ovarios poliquísticos, infertilidad y resistencia a la insulina, a las que se les administró tratamiento con metformina por 3 meses. Las pacientes que no se embarazaron en ese período recibieron tratamiento con citrato de clomifeno, hasta un máximo de 6 meses. En el Servicio de Fertilidad Maternidad "Concepción Palacios". Caracas. Resultados: Se completó un total de 62 pacientes. La tasa de embarazo de 25,8 por ciento (19 pacientes). Un 57,9 por ciento de las pacientes lograron embarazo con 3 meses de tratamiento, con una P= 0,492 lo cual no fue estadísticamente significante. La tasa de embarazos con citrato de clomifeno fue de 23,5 por ciento (8 pacientes), P=0,684. El 63,2 por ciento (12) tuvo un embarazo a término. La tasa de aborto fue de 26,3 por ciento (5). La metformina induce ovulación espontánea en pacientes con síndrome de ovarios poliquísticos. No existe diferencia estadística entre la tasa de embarazos con la terapia con metformina sola y metformina con citrato de clomifeno. La metformina mejora la evolución de embarazo

To determine the effect of treatment with metformin in infertile patients with polycystic ovary syndrome. Clinical, prospective and descriptive study. Infertile anovulatory patients with polycystic ovary syndrome and insulin resistant were included, and all of them, were treated with metformin for 3 months. Patients who did not ovulate in this time, received clomiphene citrate for 6 months. Fertility Service of Maternidad "Concepcion Palacios". 62 infertile patients were included in this study. The pregnancy rate was 25.8 percent (19 patients). The 57.9 percent of women became pregnant with metformin administration for 3 months, with P= 0.492, it was not statistical significance. The pregnancy rate with clomiphene citrate was 23.5 percent (8 patients), P= 0.684. The abortion rate was 26.3 percent (5). The metformin induce ovulation in anovulatory polycystic ovary syndrome women, whereas the pregnancy rate resulted similar in both treatment groups: metformin alone and metformin and clomiphene citrate

[Indication of metformin in the management of hormonal dysfunction secondary to polycystic ovarian syndrome: prospective comparative study about 63 cases]

Polycystic ovarian syndrome [PCOS] is the most common hormonal dysfunction in women. It's a cause of female infertility by oligoanovulation, clinical and biochemical hyperandrogenism and polycystic ovaries. Weight loss, firstly proposed in overweight or obese patient suffering from PCOS, aims to reduce hyperinsulinism and hyperandrogenism. Recently, Metformin, an insulin sensitizer, has been proposed as an alternative first line treatment for polycystic ovarian syndrome by improving hyperinsulinemia and hyperandrogenism in these women. The aim of our study, and through a literature review, is to demonstrate if Metformin should be used as a first-line drug for infertile women with this syndrome or as an adjunction to Clomifene Citrate, the longest established treatment already used in this syndrome. A prospective comparative study including 63 patients with PCOS has been done during 2 years. Women were randomly allocated to clomifene + Metformin [Metformin group, Metformin took during 8 weeks, 850 mg twice a day, plus Clomifene 100 mg per day during five days] or Clomifene only [100 mg per day during five days]. All patients underwent a two- month's diet. The middle age was about 30.63 years and the body mass index [BMI] was about 29.88 kg/ m[2]. We noticed a 6.2% weight loss in both groups [a non significant difference in p=0.04]. The median of infertility period was about 2.49 years. The ovulation rate in the Metformin group was 53.12% [significant difference for inducing ovulation p=0.02] and 32.25% in Clomifene group [non-significant difference 0.07]. There was also a significant difference for ongoing pregnancies [p=0.04]. In fact, 11 on 32 patients [34%] achieved a full-term pregnancy in Metformin group versus only 4 ones on 31 patients [12.9%] in Clomifene group. Our conclusion is that Metformin is an effective addition to Clomifene Citrate in term of reestablishment of ovulation and full-term pregnancies achievement, excluding ART cycles