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15/08/2009
José de Felippe Junior
A medicina é a fisiologia do homem doente
Atualmente dispomos de mais uma arma terapêutica para aumentar a probabilidade de gravidez nas pacientes com síndrome dos ovários policísticos: correção metabólica da hiperinsulinemia.
A correção metabólica desta síndrome na mulher jovem aumenta drasticamente as chances de engravidar e na mulher madura e idosa diminui consideravelmente o risco de obesidade, de aumento do colesterol e triglicérides, de hipertensão arterial, diabetes melitus, infarto do miocardio, doenças tromboembólicas e câncer endometrial.
A maioria das mulheres com esta síndrome e infelizmente muitos dos médicos que tratam destas pacientes não estão cientes destes riscos. Os ginecologistas pouco sabem sobre metabolismo.
A síndrome dos ovários policísticos é uma das mais comuns endocrinopatias da mulher atingindo de 4 a 6 % da população e pode ser definida como anovulação crônica androgênica. O critério diagnóstico estabelecido em 1990 pela NIH – NICHD inclui: anovulação crônica e hiperandrogenismo com exclusão de causas secundárias como hiperplasia adrenal congênita de início no adulto, hiperprolactinemia e tumor secretor de andrógenos. Não é necessária a presença de ovários policísticos para o diagnóstico.
A metformina é um composto não hormonal que afeta indiretamente a função do ovário. Ela diminui a gluneogenese hepática, diminui a absorção intestinal de carboidrato e aumenta a captação e a utilização de glicose pela periferia. A metformina provoca o aumento da sensibilidade à insulina pelos tecidos periféricos, juntamente com a redução da insulinemia, do colesterol e dos triglicérides ; ela diminui a hipertensão arterial e aumenta da atividade fibrinolítica. Nenhuma pílula anticoncapcional é capaz de fazer tanto pela paciente como a dose adequada de metformina.
Dose de metformina
Inicia-se o tratamento após verificarmos que não há espessamento de endométrio, acima de 10 mm. Se o ultrason mostrou tal espessamento procedemos à biopsia para afastar neoplasia endometrial.
Inicia-se com 500mg uma vez ao dia por 7 dias. Aumenta-se para 500 mg duas vezes ao dia após as refeições por 7 dias e depois para 850 mg duas vezes ao dia. por 3 meses. Este é o esquema usado por Scott Sills e Gianpero Palermo e segundo eles consegue restabelecer a ovulação na maioria das pacientes em 3 a 6 meses de tratamento. Algumas pacientes requerem doses superiores : 500 a 850 mg ao dia de incremento. Três meses é o período de tempo para normalizar a hiperinsulinemia e o excesso de andrógenos
Tratamento da Hiperinsulinemia
Não devemos usar somente a pílula mágica , chamada metformina, devemos sim diminuir a hiperinsulinemia com mudança salutar dos hábitos de vida :
- Exercício regular
- Alimentar-se de 3/3 horas
- Diminuir a ingestão de carboidratos refinados.
- Dieta rica em alimentos de baixo índice glicêmico
- Diminuir a carga glicêmica
- Mio-inositol
Os 6 itens acima juntamente com a metformina aumentam a eficácia do tratamento da síndrome dos ovários policísticos. A suplementação das células com os 45 nutrientes essenciais aumentará mais ainda o êxito terapêutico
Um dos grandes problemas da Medicina é que o médico trata doenças sem nenhum conhecimento de suas causas. Ele trata somente os efeitos. A lembrança a nós médicos de que somos constituídos por células é o primeiro passo para respeitar o ser humano como um ser indivisível.
Todas as células necessitam para o seu correto funcionamento da presença dos 45 nutrientes essenciais, matéria prima para a construção de todas as moléculas vitais e fortes indutores gênicos. A presença de metais tóxicos, xenobióticos e substâncias químicas estranhas atrapalham a eficiência dos nutrientes essenciais. O equilíbrio dos nutrientes coexistindo com a ausência de tóxicos no citoplasma aumenta a produção de ATP – trifosfato de adenosina – energia. Se a água citoplasmática estiver estruturada, teremos o campo ideal para a cura do processo.
A energia é o combustível usado para o funcionamento de qualquer tipo de célula, incluindo as células do ovário ( Felippe – 1990, 1994, 2000, 2001)
Para acontecer o que acabamos de descrever é necessário também que o sistema endócrino esteja em equilíbrio, incluindo uma normal insulinemia de jejum e o IGF-I em níveis corretos. Não pode haver picos ou quedas abruptos da glicemia , fato freqüente na população ocidental devido à intolerância aos carboidratos e à hipoglicemia reativa. Não pode haver excesso de sódio na dieta e falta de potássio ou magnésio.
Does metformin augment the ovulation inducing effects of clomiphene in non-obese women with polycystic ovary syndrome?
J Indian Med Assoc. 2008 Oct;106(10):643-4, 646-8
Chaudhury K, Chaudhury S, Chowdhury S.
Department of Obstetrics and Gynaecology, Chittaranjan Seva Sadan, Kolkata.
To decide if metformin augments clomiphene response for ovulation induction in non-obese women with polycystic ovary syndrome, a prospective randomised placebo-controlled trial was undertaken among 27 patients, who were found eligible for this study following clinical assessment and basic investigations. Women with polycystic ovary syndrome, even when non-obese, has increased insulin-resistance and do not respond favourably when treated with clomiphene for ovulation induction. The hypothesis is that by improving insulin- resistance and thus reversing from hyperinsulinaemia towards normal insulin secretion will enhance the responsiveness of these women to ovulation inducing effects of clomiphene. In the metformin group there were 15 patients who were given metformin 500mg orally 8 hourly daily for initial 3 months whereas in the placebo group there were 12 patients who were given folic acid (as placebo) 5mg orally once daily for initial 3 months. Thereafter, all the 27 patients in both groups were treated with clomiphene 50mg orally once daily from day 2 for 5 days in each month for subsequent 3 months. However, metformin and folic acid was continued in the metformin group and placebo group respectively for these subsequent 3 months when these patients were being treated with clomiphene for ovulation induction. Ovulation, as the outcome measure, was assessed by serial transvaginal ultrasound scanning from day 8/ day 9 and serum progesterone estimation on the 7th or 8th day following the ultrasound evidence of ovulation. Ovulation is taken to have occurred when serum progesterone was > or =8 ng/ml. Ovulation was noted to have occurred in 71.11% of the 45 cycles studied in 15 patients in the metformin group whereas ovulation occurred in 11.11% of the 36 cycles studied in 12 patients in the placebo group. This difference was highly statistically significant (p < 0.001) by Fisher's exact test. It can be conducted that metformin augments the ovulation inducing effects of clomiphene in non-obese women with polycystic ovary syndrome.
(Polycystic ovary syndrome and insulin resistance)
Rev Med Suisse. 2009 Apr 8;5(198):779-82 [Article in French]
Puder J, Pralong F.
Service d'endocrinologie, diabétologie et métabolisme, CHUV et Faculté de biologie et médecine, 1011 Lausanne.
Polycystic ovary syndrome is the most common endocrinopathy in women of reproductive age. Insulin resistance is frequently found in affected patients, and probably plays an important physiopathological role. In this paper, we will review the well recognized association between polycystic ovary syndrome and insulin resistance, and discuss the increased risk of glucose intolerance, type 2 diabetes and metabolic syndrome carried by patients diagnosed with this syndrome. We will also suggest a practical strategy for the screening and follow up of the various metabolic complications associated with polycystic ovary syndrome, in light of the rare existing recommendations of the current literature.
Drug treatments for polycystic ovary syndrome.
Am Fam Physician. 2009 Apr 15;79(8):671-6
Radosh L.
The Reading Hospital and Medical Center, Reading, Pennsylvania 19611, USA. RadoshL@readinghospital.org
Polycystic ovary syndrome is a condition present in approximately 5 to 10 percent of women of childbearing age. Diagnosis can be difficult because the signs and symptoms can be subtle and varied. These may include hirsutism, infertility, menstrual irregularities, and biochemical abnormalities, most notably insulin resistance. Treatment should target specific manifestations and individualized patient goals. When choosing a treatment regimen, physicians must take into account comorbidities and the patient's desire for pregnancy. Lifestyle modifications should be used in addition to medical treatments for optimal results. Few agents have been approved by the U.S. Food and Drug Administration specifically for use in polycystic ovary syndrome, and several agents are contraindicated in pregnancy. Insulin-sensitizing agents are indicated for most women with polycystic ovary syndrome because they have positive effects on insulin resistance, menstrual irregularities, anovulation, hirsutism, and obesity. Metformin has the most data supporting its effectiveness. Rosiglitazone and pioglitazone are also effective for ameliorating hirsutism and insulin resistance. Metformin and clomiphene, alone or in combination, are first-line agents for ovulation induction. Insulin-sensitizing agents, oral contraceptives, spironolactone, and topical eflornithine can be used in patients with hirsutism.
Metformin and polycystic ovary syndrome: a literature review.
J Obstet Gynaecol Can. 2002 May;24(5):393-401
Awartani KA, Cheung AP.
Division of Reproductive Endocrinology and Infertility, University of British Columbia, Vancouver, BC, Canada.
Polycystic ovary syndrome (PCOS) is a common endocrine condition that affects women of reproductive age. Anovulation, menstrual irregularities, hirsutism, and infertility are common clinical presentations. Long-term health concerns such as type II diabetes mellitus and, possibly, cardiovascular disease, have been linked to PCOS. Metformin, an oral hypoglycemic agent, has been recently advocated as treatment for some women with PCOS due to the association of PCOS with hyperinsulinemia. Metformin is utilized as sole therapy for ovulation induction as well as in combination with traditional ovulation-induction therapies. This review identified 23 prospective studies addressing the effects of metformin on PCOS. Because of the heterogeneity of the published reports, only a qualitative assessment of the data was possible. Review of this literature confirms a beneficial role of metformin in reducing insulin resistance in some women with PCOS. Other favourable biochemical effects include reduced free testosterone levels and increased sex hormone-binding globulin (SHBG). Metformin may improve menstrual regularity, leading to spontaneous ovulation, and improve ovarian response to conventional ovulation-induction therapies. There is, however, little evidence supporting the use of metformin to facilitate weight reduction, or improve serum lipids or hirsutism. Further evaluation is required to define the long-term effectiveness of metformin, who will benefit from metformin treatment, and the optimal duration of metformin therapy.
Metformin therapy improves the menstrual pattern with minimal endocrine and metabolic effects in women with polycystic ovary syndrome.
Fertil Steril. 1998 Apr;69(4):691-6.
Morin-Papunen LC, Koivunen RM, Ruokonen A, Martikainen HK.
Department of Obstetrics and Gynecology, University Central Hospital of Oulu, Finland.
OBJECTIVE: To determine the clinical, hormonal, and biochemical effects of 4-6 months of metformin therapy in obese patients with polycystic ovary syndrome (PCOS). DESIGN: Prospective study. SETTING: The Gynecological Endocrine Unit of University Central Hospital, Oulu, Finland. PATIENT(S): Twenty obese patients with PCOS. INTERVENTION(S): Patients were treated with 0.5 g of metformin three times daily for 4-6 months. MAIN OUTCOME MEASURE(S): Clinical symptoms, menstrual pattern, and hirsutism, as well as serum concentrations of sex steroids, sex hormone-binding globulin (SHBG), gonadotropins, and lipids were assessed during the treatment. RESULT(S): Eleven women (68.8% of the women with menstrual disturbances) experienced more regular cycles during therapy. No changes in hirsutism, body mass index, or blood pressure occurred. The mean testosterone level was decreased significantly after 2 months of treatment but returned to the starting level by 4-6 months. Free testosterone levels decreased significantly during the treatment. There was no significant change in the levels of other sex steroids or lipids measured at 4-6 months of treatment. CONCLUSION(S): Metformin therapy is well tolerated by the majority of patients and may be clinically useful, especially in obese patients with PCOS and menstrual disturbances.
Evidence-based and potential benefits of metformin in the polycystic ovary syndrome: a comprehensive review.
Endocr Rev. 2009 Feb;30(1):1-50. Epub 2008 Dec 4.
Palomba S, Falbo A, Zullo F, Orio F Jr.
Department of Gynecology and Obstetrics, University "Magna Graecia" of Catanzaro, Via Pio X, 88100 Catanzaro, Italy. stefanopalomba@tin.it
Metformin is an insulin sensitizer widely used for the treatment of patients affected by type 2 diabetes mellitus. Because many women with polycystic ovary syndrome (PCOS) are insulin resistant, metformin was introduced in clinical practice to treat these patients also. Moreover, metformin's effect has other targets beside its insulin-sensitizing action. The present review was aimed at describing all evidence-based and potential uses of metformin in PCOS patients. In particular, we will analyze the uses of metformin not only for the treatment of all PCOS-related disturbances such as menstrual disorders, anovulatory infertility, increased abortion, or complicated pregnancy risk, hyperandrogenism, endometrial, metabolic and cardiovascular abnormalities, but also for the prevention of the syndrome.
Metformin in obstetric and gynecologic practice: a review.
Obstet Gynecol Surv. 2004 Feb;59(2):118-27.
McCarthy EA, Walker SP, McLachlan K, Boyle J, Permezel M.
University of Melbourne, Department of Obstetrics and Gynaecology, Mercy Hospital for Women, East Melbourne, Australia. emecca@unimelb.edu.au
Metformin is a common treatment for women who have insulin resistance manifesting as type 2 diabetes or polycystic ovarian syndrome (PCOS). With an increasing number of these patients conceiving, it is expected that the use of metformin in and around the time of pregnancy will increase. This article reassesses the mechanisms, safety, and clinical experience of metformin use in obstetrics and gynecology. Metformin is an attractive therapeutic option because administration is simple, hypoglycemia rare, and weight loss promoted. There is a large volume of research supporting the use of metformin treatment in diabetes mellitus, androgenization, anovulation, infertility, and recurrent miscarriage. Although metformin is known to cross the placenta, there is, as yet, no evidence of teratogenicity. Metformin has an array of complex actions, accounting for the varied clinical roles, many of which are still to be fully evaluated. Much research is still needed.
Incretin hormone secretion in women with polycystic ovary syndrome: roles of obesity, insulin sensitivity, and treatment with metformin.
Metabolism. 2009 May;58(5):586-93
Svendsen PF, Nilas L, Madsbad S, Holst JJ.
Department of Obstetrics and Gynaecology, Hvidovre Hospital, Hvidovre, 2650 Hvidovre, Denmark. pernille.svendsen@hvh.regionh.dk
In normal subjects, the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are responsible for 70% of the insulin response during a meal; but in diabetic subjects and other insulin-resistant conditions, the incretin effect is impaired. Polycystic ovary syndrome (PCOS) is associated with insulin resistance, and the pathophysiologic mechanisms behind PCOS resemble those of type 2 diabetes mellitus; therefore, women with PCOS may have alterations in the incretin hormone response. Metformin is widely used in the treatment of both type 2 diabetes mellitus and PCOS. Metformin may exert some of its effect on glucose metabolism by increasing GLP-1 biosynthesis and secretion and thereby increasing the incretin effect. The objective of the study was to measure incretin hormone secretion in women with PCOS and to evaluate the effect of metformin treatment. Cross-sectional comparison of 40 women with PCOS (19 lean and 21 obese) and 26 healthy control women (9 lean and 17 obese) and longitudinal evaluation of the effects of 8 months of metformin 1000 mg twice daily in women with PCOS were performed. Plasma concentrations of GIP and GLP-1 were determined frequently during a 75-g glucose tolerance test, and insulin sensitivity was evaluated by the euglycemic hyperinsulinemic clamp. The incretin hormone response did not differ between subjects with and without PCOS. Subgroup analysis showed lower GIP (area under the curve [AUC]) levels in obese women with PCOS compared with obese control women (P < .05) and compared with lean women with PCOS (P < .05). Metformin increased GIP (AUC) and GLP-1 (AUC) in lean women with PCOS (P < .05), and a similar trend was seen in the obese women (P = .07). The GIP secretion is attenuated in obese women with PCOS, whereas treatment with metformin increases the levels of both GIP and GLP-1 in women with PCOS.
The effects of insulin sensitizers on the cardiovascular risk factors in women with polycystic ovary syndrome
J Endocrinol Invest. 2008 Dec;31(12):1124-31
Kassi E, Diamanti-Kandarakis E.
Department of Biological Chemistry, Laiko General Hospital, University of Athens Medical School, Athens, Greece.
Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in pre-menopausal women characterized by menstrual cycle disturbances, chronic anovulation, and clinical and/or biochemical hyperandrogenism. Although, the primary etiology of PCOS remains unknown, insulin resistance/hyperinsulinemia plays a pivotal role in the pathogenesis of the syndrome. A growing body of recent data support that women with PCOS have displayed an increased prevelance of cardiovascular disease (CVD) risk factors putting potentially at a hight risk for heart disease. Most of these CVD risk factors are etiologically correlated with insulin resistance/hyperinsulinemia, highlighting the role of insulin sensitizers in the therapeutic quiver for the chronic treatment of PCOS. In this review, we discuss the current literature on the CVD risk factors in PCOS and the influence of insulin sensitizers upon these risk factors.
Determinants of interleukin-6 and C-reactive protein vary in polycystic ovary syndrome, as do effects of short- and long-term metformin therapy.
Horm Res. 2009;71(3):148-54
Tsilchorozidou T, Mohamed-Ali V, Conway GS.
Department of Endocrinology, Diabetes and Metabolism, University College London Hospitals, London, UK.
OBJECTIVE, DESIGN AND METHODS: Circulating levels of interleukin-6 (IL-6) and C-reactive protein (CRP) were determined in 59 women with polycystic ovary syndrome, of whom 37 were retested after receiving metformin for 6 weeks and 6 months, to ascertain the response of these inflammatory markers to weight loss and insulin sensitization. RESULTS: IL-6 levels correlated significantly with body mass index (BMI; r = 0.55), homoeostasis model insulin resistance index (HOMA-R; r = 0.47) and CRP (r = 0.59). On multiple regression analysis, adiposity rather than IL-6 accounted for most of the variability of CRP independently of insulin resistance, while IL-6 remained closely with adiposity. After 6 weeks of metformin therapy (n = 37) there was a significant reduction in BMI (p < 0.001), waist (p < 0.001) and CRP (p < 0.01), while at 6 months there was not only a significant reduction in BMI and waist but also in HOMA-R (p = 0.01) and IL-6 levels (p < 0.01) with no further reduction of CRP. CONCLUSIONS: In polycystic ovary syndrome, obesity rather than IL-6 or insulin resistance is the main determinant of CRP. While short-term metformin therapy facilitates weight loss with a concomitant reduction in CRP, long-term therapy results in a reduction of IL-6 and insulin resistance. Metformin-associated reduction of CRP levels prior to any significant changes in insulin resistance or IL-6 perhaps involves different mechanisms of action. Copyright 2009 S. Karger AG, Basel.
Insulin resistance, polycystic ovary syndrome and metformin.
Drugs. 1999;58 Suppl 1:41-6; discussion 75-82
Pugeat M, Ducluzeau PH.
Clinique Endocrinologique, Hôpital de l'Antiquaille and INSERM U329, France. mrichard@cismsun.univ-lyon1.fr
Polycystic ovary syndrome (PCOS) is the most common disorder of ovarian function in premenopausal women. PCOS is characterised by chronic anovulation and androgen excess with clinical manifestation of irregular menstrual cycles, hirsutism and/or acne. Insulin resistance with resultant hyperinsulinaemia, irrespective of excess weight or frank obesity, has been reported in patients with PCOS, and, as insulin has a direct effect on ovarian androgen production in vitro, insulin resistance may play a crucial role in the physiopathology of PCOS. Although the molecular mechanism(s) of insulin resistance in PCOS is unclear, excessive insulin-independent serine phosphorylation of the beta subunit of the insulin receptor, as reported in some patients with PCOS, has been put forward as a new mechanism for insulin resistance. Insulin-sensitising agents have recently been investigated for their role in the short term treatment of insulin resistance in PCOS. Controlled studies have shown that metformin administration, by promoting bodyweight loss, can decrease fasting and stimulated plasma insulin levels. However, other studies have shown metformin 500 mg 3 times daily to decrease insulin secretion and to reduce ovarian production of 17alpha-hydroxyprogesterone with recovery of spontaneous or clomifene-induced ovulation, independently of weight loss. These findings suggest a new indication for metformin and present insulin-sensitising agents as a novel approach in the treatment of ovarian hyperandrogenism and abnormal ovulation in PCOS. They also suggest that long term administration of metformin might be helpful in treating insulin resistance, thus reducing risks of type 2 (non-insulin-dependent) diabetes and cardiovascular disease in these patients.
Use of metformin in polycystic ovary syndrome.
Am J Obstet Gynecol. 2008 Dec;199(6):596-609.
Mathur R, Alexander CJ, Yano J, Trivax B, Azziz R.
Department of Obstetrics/Gynecology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Women with polycystic ovary syndrome (PCOS) have a myriad of phenotypic and clinical features that may guide therapeutic options for metabolic protection and ovulation induction. The use of metformin may prove beneficial in a subset of the population of women with PCOS. Hyperinsulinemia, as demonstrated by elevated insulin levels on a 2-hour 75-g load glucose tolerance test, is an important parameter in deciding whether or not to initiate metformin therapy to women with PCOS with the hope of preventing or delaying the onset of type 2 diabetes mellitus (DM). Cardiovascular risk factors including markers of subclinical inflammation, and dyslipidemia may also be improved by metformin therapy. For ovulation induction, metformin is not as effective as clomiphene citrate as first-line therapy for women with PCOS. There are no clear data to suggest that metformin reduces pregnancy loss or improves pregnancy outcome in PCOS, and it is currently recommended that metformin be discontinued with the first positive pregnancy test result, unless there are other medical indications (eg, type 2 DM). This review addresses practical management guidelines for the uses of metformin in women with PCOS.
PMID: 19084097 [PubMed - indexed
Evidence-based and potential benefits of metformin in the polycystic ovary syndrome: a comprehensive review.
Endocr Rev. 2009 Feb;30(1):1-50.
Palomba S, Falbo A, Zullo F, Orio F Jr.
Department of Gynecology and Obstetrics, University "Magna Graecia" of Catanzaro, Via Pio X, 88100 Catanzaro, Italy. stefanopalomba@tin.it
Metformin is an insulin sensitizer widely used for the treatment of patients affected by type 2 diabetes mellitus. Because many women with polycystic ovary syndrome (PCOS) are insulin resistant, metformin was introduced in clinical practice to treat these patients also. Moreover, metformin's effect has other targets beside its insulin-sensitizing action. The present review was aimed at describing all evidence-based and potential uses of metformin in PCOS patients. In particular, we will analyze the uses of metformin not only for the treatment of all PCOS-related disturbances such as menstrual disorders, anovulatory infertility, increased abortion, or complicated pregnancy risk, hyperandrogenism, endometrial, metabolic and cardiovascular abnormalities, but also for the prevention of the syndrome.
Polycystic ovary syndrome: treatment strategies and management Expert Opin Pharmacother. 2008 Dec;9(17):2995-3008
Escobar-Morreale HF.
University of Alcalá, Hospital Universitario Ramón y Cajal, Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Department of Endocrinology, Madrid, Spain. hescobarm.hrc@salud.madrid.org
BACKGROUND: The polycystic ovary syndrome (PCOS) is possibly the most common endocrine disorder in premenopausal women, with prevalences in the 6-7% range reported worldwide. Although PCOS is primarily a disorder of androgen excess, affected women frequently present with abdominal adiposity and insulin resistance, explaining the association of PCOS with metabolic comorbidities and an increased cardiovascular risk. Abdominal adiposity, and very especially the compensatory hyperinsulinism resulting from insulin resistance, further contribute to hyperandrogenism. These pathophysiological mechanisms must be considered when deciding the optimal therapy for PCOS patients. OBJECTIVE: To review the impact of the current approaches to the treatment of PCOS on the metabolic associations and the cardiovascular risk of these women. METHODS: Review of published studies addressing the effects of different treatment strategies of PCOS. Results: The resolution of PCOS after the marked and sustained weight loss attained after bariatric surgery makes this therapeutic option a first-line strategy in women presenting with severe obesity. In patients with lesser grades of obesity who desire fertility, a short trial of metformin, followed by classic ovulation induction and/or assisted reproductive techniques in case pregnancy is not achieved in a few months, is a reasonable approach. If fertility is not an immediate concern, third generation oral contraceptive pills containing a neutral or antiandrogenic progestin remains the drug of choice, considering their efficacy, their excellent tolerability, and their overall metabolic safety. Conclusion: Strategies targeting obesity and abdominal adiposity, insulin resistance and hyperandrogenism, alone or in combination, are effective in ameliorating the signs and symptoms of hyperandrogenism while improving the metabolic comorbidities and the cardiovascular risk of these patients in most cases.
Metformin Therapy Increases Insulin-Stimulated Release of D-Chiro-Inositol-Containing Inositolphosphoglycan Mediator in Women with Polycystic Ovary Syndrome
The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 1 242-249
Jean-Patrice Baillargeon, Maria J. Iuorno, Daniela J. Jakubowicz, Teimuraz Apridonidze, Na He and John E. Nestler
Department of Medicine (J.-P.B.), Université de Sherbrooke, Sherbrooke, J1H SN4 Canada; Departments of Medicine (M.J.I., T.A., N.H., J.E.N.) and Obstetrics and Gynecology (J.E.N.), Virginia Commonwealth University, Richmond, Virginia 23298-0111; and Hospital de Clinicas Caracas (D.J.J.), 1040 Caracas, Venezuela
Some actions of insulin are mediated by putative inositolphosphoglycan mediators, and a deficiency in D-chiro-inositol-containing inositolphosphoglycan (DCI-IPG) may contribute to insulin resistance in women with polycystic ovary syndrome (PCOS). Furthermore, similar effects of DCI and metformin, an insulin-sensitizing drug, have been demonstrated in PCOS women. To determine whether metformin improves insulin actions by increasing biologically active DCI-IPG in women with PCOS, we analyzed DCI-IPG during an oral glucose tolerance test in 19 obese women with PCOS before and after 4–8 wk of metformin or placebo. After treatment, the mean (±SE) area under the curve (AUC) during the oral glucose tolerance test of insulin (AUCinsulin) decreased significantly more in the metformin group, compared with the placebo group [-3574 ± 962 vs. +1367 ± 1021 µIU/min·ml (-26 ± 7 vs. +10 ± 7 nmol/min·liter), P = 0.003], but the AUC of DCI-IPG (AUCDCI-IPG) decreased similarly in both groups (-1452 ± 968 vs. -2207 ± 1021%/min, P = 0.60). However, the ratio of AUCDCI-IPG/AUCinsulin increased by 160% after metformin and decreased by 29% after placebo (P = 0.002 between groups). Moreover, metformin seemed to improve the positive correlation between AUCDCI-IPG and AUCinsulin but not placebo (r = 0.32, P = 0.68 at baseline; r = 0.52, P = 0.12 after metformin; and r = -0.39, P = 0.30 after placebo). We conclude that in obese women with PCOS, metformin may improve the action of insulin in part by improving insulin-mediated release of DCI-IPG mediators, as evidenced by increased bioactive DCI-IPG released per unit of insulin.
Insulin-sensitising drugs (metformin, troglitazone, rosiglitazone, pioglitazone, D-chiro-inositol) for polycystic ovary syndrome.
Cochrane Database Syst Rev. 2003;(3):CD003053.
Comment in:
ACP J Club. 2004 May-Jun;140(3):75.
Update in:
Cochrane Database Syst Rev. 2009;(3):CD003053.
Lord JM, Flight IH, Norman RJ.
Department of Endocrinology and Metabolism, Peninsula Medical School, South West Centre for Reproductive Medicine, Derriford Hospital, Plymouth, Devon, UK, PL6 8DH.
BACKGROUND: Polycystic ovary syndrome (PCOS) is characterised by anovulation, hyperandrogenaemia and insulin resistance. Hyperinsulinaemia is known to be associated with an increase in cardiovascular risk and the development of diabetes mellitus. If insulin sensitising agents such as metformin are effective in treating features of PCOS, then they could have wider health benefits than just treating the symptoms of the syndrome. OBJECTIVES: To assess the effectiveness of insulin sensitising drugs in improving clinical and biochemical features of PCOS. SEARCH STRATEGY: We searched the Cochrane Menstrual Disorders & Subfertility Group trials register (December 2002), the Cochrane Central Register of Controlled Trials (Cochrane Library, Issue 4, 2002), MEDLINE (January 1966 to December 2002), and EMBASE (January 1985 to December 2002). SELECTION CRITERIA: Randomised controlled trials which investigated the effect of insulin sensitising drugs compared with either placebo or no treatment, or compared with an ovulation induction agent. DATA COLLECTION AND ANALYSIS: Performed by two reviewers, one blinded to information that could have identified the authors, publisher or results of each study. Fifteen trials were included for analysis, 13 of them using metformin and involving 543 participants. MAIN RESULTS: Meta-analysis showed that metformin is effective in achieving ovulation in women with PCOS with odds ratios of 3.88 (CI 2.25 to 6.69) for metformin versus placebo and 4.41 (CI 2.37 to 8.22) for metformin and clomifene versus clomifene alone. An analysis of pregnancy rates suggests a significant treatment effect for metformin and clomifene (OR 4.40, CI 1.96 to 9.85). Metformin has a significant effect in reducing fasting insulin levels (WMD -5.37, CI -8.11 to -2.63), blood pressure and low-density lipoprotein cholesterol (LDL). There was no evidence of effect on body mass index or waist:hip ratio. Metformin was associated with a significantly higher incidence of nausea, vomiting and other gastrointestinal disturbance, but no serious adverse effects were reported. REVIEWER'S CONCLUSIONS: Metformin is an effective treatment for anovulation in women with PCOS. Its choice as a first line agent seems justified, and there is some evidence of benefit on parameters of the metabolic syndrome. Ovulation rates are higher when combined with clomifene (76% versus 46% when used alone), but there is no evidence to indicate whether there is an increased multiple pregnancy rate with this combination. There is no data regarding its safety in long-term use in young women. It should be used as an adjuvant to general lifestyle improvements, and not as a replacement for increased exercise and improved diet.
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