Pioglitazone and metformin in obese women with polycystic ovary syndrome not optimally responsive to metformin. Metformin reduces pregnancy complications without affecting androgen levels in pregnant polycystic ovary syndrome women: results of a randomized study. Effects of metformin on spontaneous and clomiphene-induced ovulation in the polycystic ovary syndrome. Effect of flutamide and metformin administered alone or in combination in dieting obese women with polycystic ovary syndrome Effect of long-term treatment with metformin added to hypocaloric diet on body composition, fat distribution, and androgen and insulin levels in abdominally obese women with and without the polycystic ovary syndrome. Sequential treatment of metformin and clomiphene citrate in clomiphene-resistant women with polycystic ovary syndrome: a randomized, controlled trial. Ethinylestradiol-drospirenone, flutamide-metformin, or both for adolescents and women with hyperinsulinemic hyperandrogenism: opposite effects on adipocytokines and body adiposity. Nonobese women with polycystic ovary syndrome respond better than obese women to treatment with metformin. The effects of metformin on insulin resistance, clomiphene-induced ovulation and pregnancy rates in women with polycystic ovary syndrome. Metformin or antiandrogen in the treatment of hirsutism in polycystic ovary syndrome. Metformin treatment before IVF/ICSI in women with polycystic ovary syndrome; a prospective, randomized, double blind study. Height, weight, and motor-social development during the first 18 months of life in 126 infants born to 109 mothers with polycystic ovary syndrome who conceived on and continued metformin through pregnancy. Six-month treatment with low-dose dexamethasone further reduces androgen levels in PCOS women treated with diet and lifestyle advice, and metformin. Medical vs. surgical treatment for clomiphene citrate-resistant women with polycystic ovary syndrome The role of metformin in the management of polycystic ovary syndrome Effects of metformin therapy on hyperandrogenism in women with polycystic ovarian syndrome Effects of metformin on clinical and biochemical parameters in polycystic ovary syndrome. Metformin reduces serum C-reactive protein levels in women with polycystic ovary syndrome. [Metformin, an efficacious drug in the treatment of polycystic ovary syndrome]. The effect of metformin on ovarian stimulation and in vitro fertilization in insulin-resistant women with polycystic ovary syndrome: an open-label randomized cross-over trial Effect of rosiglitazone on spontaneous and clomiphene citrate-induced ovulation in women with polycystic ovary syndrome. The effect of metformin treatment to ovarian response in cases with PCOS Ghrelin and measures of satiety are altered in polycystic ovary syndrome but not differentially affected by diet composition. Metformin administration modulates and restores luteinizing hormone spontaneous episodic secretion and ovarian function in nonobese patients with polycystic ovary syndrome. Comparison of efficacy of spironolactone with metformin in the management of polycystic ovary syndrome: an open-labeled study.
BACKGROUND In an observational study of 13 women with polycystic ovary syndrome ( PCOS ) not optimally responsive to metformin diet  , we assessed the efficacy and safety of addition of pioglitazone . We also compared these 13 women to 26 women with PCOS , who were responsive to metformin diet , matched by age and by pre- treatment menstrual history and not different by obesity categories . METHODS Prospect ively , as out patients , with diet constant [ 1500 - 2000 calorie ( depending on entry body mass index ) , 26 % protein , 44 % carbohydrate , 30 % fat ] , metformin ( 2.55 g/day ) was given for 12 months to 39 women , 13 not optimally responsive , 26 responsive to metformin diet  , followed by addition of pioglitazone ( 45 mg/day ) for 10 months in the 13 non-responders . Outcome measures included changes in sex hormones , insulin , insulin resistance ( IR ) , insulin secretion , high density lipoprotein cholesterol , weight , and menstrual status . RESULTS In 13 non-responders , on metformin diet , median serum insulin fell ( 21 to 16 microIU/ml , P<0.05 ) and insulin secretion fell from 251 to 200 ( P<0.01 ) ; weight , dehydroepi and rosterone sulphate ( DHEAS ) , testosterone and IR were unchanged ( P > or = 0.07 ) . Compared with 14 % pre- treatment , on metformin diet , expected menses occurred 46 % of the time at 3 months ( P=0.05 ) , 38 % at 6 months ( P=0.07 ) , 27 % at 9 months , and 24 % at 12 months . In 26 responders , on metformin diet , median weight fell ( 93 to 87 kg ) , testosterone fell ( 50 to 32 ng/dl ) , insulin fell ( 26 to 16 microIU/ml ) , IR fell ( 5.32 to 3.45 ) and insulin secretion fell ( 351 to 271 ) ( P < or = 0.017 for all ) . The occurrence of expected menses in the 26 responders was 2.5-fold higher than in the 13 non-responders ( P<0.0001 ) . In 11 non-responders , on pioglitazone + metformin diet over 10 months versus antecedent metformin diet , DHEAS fell ( 211 to 171 microg/dl , P=0.02 ) , insulin fell ( 16 to 10 microIU/ml , P= 0.001 ) , IR fell ( 3.37 to 1.73 , P=0.002 ) , insulin secretion fell ( 217 to 124 , P=0.004 ) , sex hormone-binding globulin rose ( 31 to 43 nmol/l , P=0.006 ) , and HDL cholesterol rose ( 38 to 42 mg/dl , P=0.003 ) . On pioglitazone + metformin diet , the occurrence of expected menses was 2-fold higher than on metformin diet ( P<0.0001 ) . CONCLUSIONS In women with PCOS who failed to respond optimally to metformin , when pioglitazone was added , insulin , glucose , IR , insulin secretion , and DHEAS fell , HDL cholesterol and sex hormone-binding globulin rose , and menstrual regularity improved , without adverse side-effects BACKGROUND Investigation of a possible effect of metformin on and rogen levels in pregnant women with polycystic ovary syndrome ( PCOS ) . METHODS A prospect i ve , r and omized , double-blind , placebo-controlled pilot study was conducted . Forty pregnant women with PCOS received diet and lifestyle counselling  and were r and omized to either metformin 850 mg twice daily or placebo . Primary outcome measures were changes in serum levels of dehydroepi and rosterone sulphate , and rostenedione , testosterone , sex hormone-binding globulin , and free testosterone index . Secondary outcome measures were pregnancy complications and outcome . Two-tailed t-tests and chi2-tests were used . RESULTS Maternal and rogen levels were unaffected by metformin treatment in pregnant women with PCOS . While none of the 18 women in the metformin group experienced a severe pregnancy or post-partum complication , seven of the 22 ( 32 % ) women experienced severe complications in the placebo group ( P = 0.01 ) . CONCLUSIONS Metformin treatment did not reduce maternal and rogen levels in pregnant women with PCOS . In the metformin-treated group we observed a reduction of severe , pregnancy and post-partum complications .  Metformin treatment of pregnant PCOS women may reduce complications during pregnancy and in the post-partum period BACKGROUND Obese women with the polycystic ovary syndrome are relatively unresponsive to the induction of ovulation by clomiphene . We hypothesized that reducing insulin secretion by administering metformin would increase the ovulatory response to clomiphene . METHODS We performed oral glucose-tolerance tests before and after the administration of 500 mg of metformin or placebo three times daily for 35 days in 61 obese women with the polycystic ovary syndrome . Women who did not ovulate spontaneously were then given 50 mg of clomiphene daily for five days while continuing to take metformin or placebo .  Serum progesterone was measured on days 14 , 28 , 35 , 44 , and 53 , and ovulation was presumed to have occurred if the concentration exceeded 8 ng per milliliter ( 26 nmol per liter ) on any of these days . RESULTS Twenty-one women in the metformin group and 25 women in the placebo group were given clomiphene because they did not ovulate spontaneously during the first phase of the study . Among the 21 women given metformin plus clomiphene , the mean ( + /-SE ) area under the serum insulin curve after oral glucose administration decreased from 6745+/-2021 to 3479+/-455 microU per milliliter per minute ( 40.5+/-12.1 to 20.9+/-2.7 nmol per liter per minute , P=0.03 ) , but it did not change significantly in the 25 women given placebo plus clomiphene . Nineteen of the 21 women ( 90 percent ) who received metformin plus clomiphene  ovulated ( mean peak serum progesterone concentration , 23.8+/-3.4 ng per milliliter [ 7.6+/-10.9 nmol per liter ] ) . Two of the 25 women ( 8 percent ) who received placebo plus clomiphene  ovulated ( P<0.001 ) . Overall , 31 of the 35 women ( 89 percent ) treated with metformin  ovulated spontaneously or in response to clomiphene  , as compared with 3 of the 26 women ( 12 percent ) treated with placebo . CONCLUSIONS The ovulatory response to clomiphene can be increased in obese women with the polycystic ovary syndrome by decreasing insulin secretion with metformin background Hyper and rogenism , hyperinsulinaemia and obesity play a key and coordinating roles in the pathogenesis of polycystic ovary syndrome ( PCOS ) , contributing in different ways to the clinical expression of the syndrome . Weight loss is beneficial , but the additional administration of insulin‐lowering drugs , such as metformin , and anti and rogens may produce further benefits , due to their different spectrum of action . The effects of long‐term metformin and flutamide , an anti and rogen drug , added alone or in combination with a low‐calorie diet , on body weight and fat distribution , and rogens , metabolic parameters and clinical status in obese women with PCOS were investigated Abdominal obesity and hyperinsulinemia play a key role in the development of the polycystic ovary syndrome ( PCOS ) . Dietary-induced weight loss and the administration of insulin-lowering drugs , such as metformin , are usually followed by improved hyper and rogenism and related clinical abnormalities . This study was carried out to evaluate the effects of combined hypocaloric diet and metformin on body weight , fat distribution , the glucose-insulin system , and hormones in a group of 20 obese PCOS women [ body mass index ( BMI ) > 28 kg/m2 ] with the abdominal phenotype ( waist to hip ratio > 0.80 ) , and an appropriate control group of 20 obese women who were comparable for age and pattern of body fat distribution but without PCOS . At baseline , we measured sex hormone , sex hormone-binding globulin ( SHBG ) , and leptin blood concentrations and performed an oral glucose tolerance test and computerized tomography ( CT ) at the L4-L5 level , to measure sc adipose tissue area ( SAT ) and visceral adipose tissue area . All women were then given a low-calorie diet ( 1,200 - 1,400 kcal/day ) alone for one month , after which anthropometric parameters and CT scan were newly measured . While continuing dietary treatment , PCOS women and obese controls were subsequently placed , in a r and om order , on metformin ( 850 mg/os , twice daily ) ( 12 and 8 , respectively ) or placebo ( 8 and 12 , respectively ) , according to a double-blind design , for the following 6 months . Blood tests and the CT scan were performed in each woman at the end of the study while they were still on treatment . During the treatment period , 3 women of the control group ( all treated with placebo ) were excluded because of noncompliance ; and 2 PCOS women , both treated with metformin , were also excluded because they became pregnant . Therefore , the women cohort available for final statistical analysis included 18 PCOS ( 10 treated with metformin and 8 with placebo ) and 17 control women ( 8 treated with metformin and 9 with placebo )  . The treatment was well tolerated . In the PCOS group , metformin therapy improved hirsutism and menstrual cycles significantly more than placebo .  Baseline anthropometric and CT parameters were similar in all groups . Hypocaloric dieting for 1 month similarly reduced BMI values and the waist circumference in both PCOS and control groups , without any significant effect on CT scan parameters . In both PCOS and control women , however , metformin treatment reduced body weight and BMI significantly more than placebo . Changes in the waist-to-hip ratio values were similar in PCOS women and controls , regardless of pharmacological treatment . Metformin treatment significantly decreased SAT values in both PCOS and control groups , although only in the latter group were SAT changes significantly greater than those observed during the placebo treatment . On the contrary , visceral adipose tissue area values significantly decreased during metformin treatment in both PCOS and control groups , but only in the former was the effect of metformin treatment significantly higher than that of placebo .  Fasting insulin significantly decreased in both PCOS women and controls , regardless of treatment , whereas glucose-stimulated insulin significantly decreased only in PCOS women and controls treated with metformin . Neither metformin or placebo significantly modified the levels of LH , FSH , dehydroepi and rosterone sulphate , and progesterone in any group , whereas testosterone concentrations decreased only in PCOS women treated with metformin .  SHBG concentrations remained unchanged in all PCOS women ; whereas in the control group , they significantly increased after both metformin and placebo .  Leptin levels decreased only during metformin treatment in both PCOS and control groups . ( ABSTRACT TRUNCATED BACKGROUND Recognition of the importance of insulin resistance in clomiphene-resistant women with polycystic ovary syndrome ( PCOS ) has led to the use of insulin sensitizers . METHODS A r and omized , controlled trial was conducted to compare efficacy of sequential treatment with metformin and clomiphene citrate with conventional gonadotrophins .  Sixty clomiphene-resistant women with PCOS were r and omized to two groups ( n = 30 each ) , using computer-generated tables . Group I received metformin for 6 months , followed by ovulation induction with clomiphene citrate ; group II received hMG for ovulation induction . Hormonal profiles were evaluated at the onset and after completion of treatment . RESULTS There was no significant difference in pregnancy rates between the two groups ( 16.7 versus 23.3 % ) . In group I , there was a significant improvement in menstrual function and ovulation after treatment ( 40 % , P < 0.001 ; and 46.7 % , P < 0.001 ) , with a significant decrease in fasting insulin levels ( P < 0.05 ) . There were no changes in other biochemical parameters . The ovulation rate in group II was 43.3 % , with a high drop-out rate . The cost-effective analysis for medications per pregnancy in group I was US$ 71 + /- 3 versus US$ 277 + /- 171 in group II . CONCLUSIONS Sequential treatment with metformin and clomiphene citrate is an effective and safe option for clomiphene-resistant women with PCOS Hyperinsulinemic hyper and rogenism with anovulation , the so-called polycystic ovary syndrome ( PCOS ) , is the most frequent endocrine disorder of young women . One of the stigmata of PCOS is a deficit of lean mass and an excess of fat , in particular , abdominal fat , even in the absence of obesity . Adiponectin and IL-6 are among the adipocytokines that have recently been related to abdominal fat excess , insulin resistance states , and cardiovascular disease risk . We studied the effects of two new treatment options , ethinylestradiol-drospirenone and flutamide-metformin , and of their combination on adipocytokinemia and body adiposity in adolescents and women with PCOS . Adolescents with PCOS ( n = 32 ; age , approximately 15 yr ; body mass index , approximately 22 kg/m(2 ) ) were r and omly assigned to receive the oral contraceptive ( OC ) ethinylestradiol-drospirenone , or the low-dose generic duo of flutamide ( 62.5 mg/d ) plus metformin ( 850 mg/d ) . Young women with PCOS ( n = 22 ; age , approximately 19 yr ; body mass index , approximately 22 kg/m(2 ) ) were r and omized to receive the same OC , either alone or with flutamide-metformin .  Fasting blood glucose , serum insulin , lipids , and rogens , IL-6 , adiponectin , and body composition ( by absorptiometry ) were assessed at the start , and after 3 and /or 9 months . At the start , serum concentrations of the proinflammatory IL-6 were high , and those of the antiinflammatory adiponectin were low ; body composition was adipose in each sub population . Abnormal adipocytokine levels , hypertriglyceridemia , and body adiposity diverged further from the norm in adolescents on OC ; in contrast , girls on flutamide-metformin reverted all study indices toward normal , lost part of their fat excess , and reduced their lean mass deficit . In comparison to the girls on OC , those on flutamide-metformin lost a mean of approximately 4 kg of fat and gained approximately 4 kg of lean mass . Similarly , abnormal adipocytokine levels and adiposity were aggravated in women on OC alone and improved in women on OC plus flutamide-metformin ; within 9 months , the latter subgroup lost a mean of approximately 3 kg of fat and gained approximately 3 kg of lean mass , in comparison to women on OC alone . In conclusion , young and nonobese PCOS patients were found to be in a low- grade , chronic inflammation state , and to have a body adiposity that evolves according to the balance of circulating adipocytokines and lipids , rather than to and rogen excess or fasting hyperinsulinemia . Monotherapy with ethinylestradiol-drospirenone may not be a prime choice for PCOS , given its inefficacy to attenuate abnormal adipocytokine levels and body adiposity ;  ethinylestradiol-drospirenone plus flutamide-metformin , however , is a first OC combination that was found capable of reverting both the adipocytokine balance and the body composition toward normal , and that may therefore improve the long-term cardiovascular perspectives of women with PCOS OBJECTIVE To determine the clinical , hormonal , and biochemical effects of metformin therapy in obese and nonobese patients with polycystic ovary syndrome ( PCOS ) . DESIGN Controlled clinical study . SETTING Department of Gynecology of Federal University of São Paulo , São Paulo , Brazil . PATIENT(S ) Twenty-nine patients with PCOS . INTERVENTION(S ) Patients were treated with 500 mg of p.o . metformin t.i.d . for 6 months . MAIN OUTCOME MEASURE(S ) Clinical data as well as serum concentrations of sex steroids , sex hormone-binding globulin ( SHBG ) , gonadotropins , leptin , GH , lipids , insulin , and glucose levels were assessed before and after treatment . RESULT ( S ) In the metformin group of nonobese patients , the mean fasting serum insulin concentration decreased from a pretreatment value of 12.1 + /- 2.4 to 6.3 + /- 0.6 microU/mL after treatment , and the area under the curve of insulin decreased from 5,189.1 + /- 517.4 to 3,035.6 + /- 208.9 microU/mL per minute . Also in the metformin group of nonobese patients , the mean basal serum total testosterone , free testosterone , and and rostenedione concentrations decreased by 38 % , 58 % , and 30 % , respectively . In the obese patients treated with metformin , only free testosterone showed a statistically significant decrease ( 1.7 + /- 0.2 ) . CONCLUSION ( S ) Our data suggest that nonobese patients respond better than obese patients to a 1.5 g/day metformin regimen OBJECTIVE ( S ) To evaluate the effects of metformin on insulin resistance , ovarian and rogen production , and clomiphene-induced ovulation and pregnancy rates in infertile women with polycystic ovary syndrome ( PCOS ) . STUDY DESIGN Twenty-one infertile women with PCOS were selected in this prospect i ve r and omized clinical study . Basal steroid and gonadotropin levels were measured , and oral glucose tolerance test ( OGTT ) was performed . The patients were divided r and omly into group 1 ( n = 11 ) and group 2 ( n = 10 ) . Group 1 patients were treated with 1700 mg per day of metformin for 3 months . The basal tests and OGTT were repeated after metformin therapy . Group 2 patients did not receive metformin . The patients in both groups received 100 mg of clomiphene citrate ( CC ) daily for 5 days until either a pregnancy occurred , or six CC cycles were reached . Metformin administration continued during CC therapy until the day of hCG in group 1 . Serum progesterone ( P ) level > or=5 ng/ml was considered as confirmatory of ovulation . Ovulation and pregnancy rates after six cycles were determined . RESULTS Serum and rogens and insulin response to OGTT decreased significantly after metformin therapy . Midluteal serum P level was significantly higher in cycles treated with metformin plus CC ( P < 0.05 ) . The ovulation ( 38 of 51 cycles , 74.4 % versus 34 of 55 cycles , 61.8 % ) and pregnancy rates ( 5 of 11 women , 45.5 % versus 3 of 10 women , 30 % ) were higher , but not significantly , in the metformin plus CC group than in the CC alone group . All the patients who conceived had insulin resistance in group 1 whereas non-insulin resistance in group 2 . CONCLUSION ( S ) Metformin improves insulin resistance and reduces and rogen levels .  Metformin did not increase significantly the ovulation and pregnancy rates Hirsutism is a common and distressing symptom frequently encountered in women with polycystic ovary syndrome ( PCOS ) , who also show relative insulin resistance . The aim of this trial , in which hirsutism was the primary end point , was to compare the efficacy of the oral antihyperglycemic medication metformin with that of an established treatment , combined ethinyl estradiol and cyproterone acetate .  Patients ( n = 52 ) were r and omized to receive either metformin ( 500 mg , three times daily ) or Dianette ( ethinyl estradiol , 35 micro g ; cyproterone acetate , 2 mg ) treatment for 12 months , with assessment s before treatment , at 6 months , and at 12 months . Both objective and subjective methods of evaluating hirsutism were used , and in addition , patient perceptions were examined . The results show that metformin is potentially an effective treatment for moderate to severe hirsutism in women with PCOS . They also suggest that in some respects ( Ferriman-Gallwey score and patient self- assessment ) , it is more efficacious than the st and ard treatment ( Dianette ) . The objective evaluation of hair diameter reduction showed that both treatments were moderately effective at multiple anatomical sites . Dianette treatment was responsible for profound suppression of and rogen activity , in contrast to metformin , which induced negligible change . However , metformin did reduce markers of insulin resistance . The data suggest that hirsutism may be effectively treated by reducing hyperinsulinemia BACKGROUND Our aim was to investigate the effect of pre-treatment with metformin in women with polycystic ovary syndrome ( PCOS ) scheduled for IVF stimulation . METHODS Seventy-three oligo/amenorrhoeic women with polycystic ovaries and at least one of the following criteria : hyper and rogenaemia , elevated LH/FSH ratio , hyperinsulinism , decreased SHBG levels or hirsutism , were studied . Normal weight and overweight patients were r and omized separately in a prospect i ve , r and omized , double blind study . All patients were treated for at least 16 weeks with metformin ( 1000 mg bid ) or placebo ending on the day of HCG injection . RESULTS No differences were found in the primary end-points : duration of FSH stimulation 14.4 ( 13.1 - 15.7 ) versus 14.2 ( 12.6 - 15.7 ) days or estradiol on the day of HCG injection 6.8 ( 5.3 - 8.2 ) versus 7.6 ( 5.6 - 9.6 ) nmol/l in the metformin and placebo groups , respectively . The secondary end-points number of oocytes , fertilization rates , embryo quality , pregnancy rates and clinical pregnancy rates were equal . However , in the normal weight subgroup ( BMI < 28 kg/m(2 ) , n = 27 ) , pregnancy rates following IVF were 0.71 ( 0.63 - 0.79 ) versus 0.23 ( 0.15 - 0.31 ) in the metformin and placebo groups , respectively ( P = 0.04 ) . Overall clinical pregnancy rates were equal : 0.51 ( 0.34 - 0.68 ) versus 0.44 ( 0.27 - 0.62 ) in the metformin and placebo groups , respectively . However , in the normal weight subgroup , clinical pregnancy rates were 0.67 ( 0.43 - 0.91 ) and 0.33 ( 0.06 - 0.60 ) , respectively ( P = 0.06 ) . CONCLUSIONS Pre-treatment with metformin prior to conventional IVF/ICSI in women with PCOS does not improve stimulation or clinical outcome . However , among normal weight PCOS women , pre-treatment with metformin tends to improve pregnancy rates . Further studies in subgroups of PCOS women are required BACKGROUND We prospect ively assessed growth and motor-social development during the first 18 months of life in 126 live births ( 122 pregnancies ) to 109 women with polycystic ovary syndrome ( PCOS ) who conceived on and continued metformin ( 1.5 - 2.55 g/day ) through pregnancy . METHODS The lengths and weights of PCOS neonates were compared with gender-specific Centers for Disease Control and Prevention ( CDC ) infant data . Gestational diabetes ( GD ) and pre-eclampsia in women with PCOS were compared with 252 healthy women without PCOS who had > or=1 live birth ( 262 live births ) . RESULTS There were 101 out of 126 ( 80 % ) term ( > or=37 gestational weeks ) PCOS births , which was not significantly different ( P = 0.7 ) from controls , 206 out of 252 ( 81.7 % ) . There were two ( 1.6 % ) birth defects . GD occurred in nine out of 119 PCOS pregnancies ( 7.6 % ) versus 40 out of 251 ( 15.9 % ) controls , P = 0.027 . The prevalence of pre-eclampsia did not differ in PCOS versus control pregnancies ( 4.1 versus 3.6 % , P = 0.8 ) . The birth length and weight of the 52 male neonates did not differ ( P > 0.05 ) from those of CDC males ; the 74 female neonates were shorter than CDC females ( 48.9 + /- 5.4 versus 50.6 + /- 2.7 cm , P = 0.006 ) and weighed less ( 3.09 + /- 0.85 versus 3.29 + /- 0.52 kg , P = 0.04 ) . There were no systematic differences in growth between PCOS and CDC infants over 18 months . At 3 , 6 , 9 , 12 and 18 months , of a potential 100 % motor-social development score , scores ( + /-SD ) were 95 + /- 13 , 98 + /- 8 % , 95 + /- 10 , 97 + /- 8 and 94 + /- 16 % ; no infants had motor-social developmental delays . CONCLUSIONS Metformin reduced development of GD , was not teratogenic and did not adversely affect birth length and weight , growth or motor-social development in the first 18 months of life BACKGROUND The purpose of this study was to investigate the effect of low-dose dexamethasone on and rogen levels in women with polycystic ovary syndrome ( PCOS ) treated with diet and lifestyle counselling , and metformin .  METHODS A prospect i ve , r and omized , double blind , placebo-controlled study was carried out . Thirty-eight women with PCOS were r and omized to either dexamethasone 0.25 mg daily or placebo for 26 weeks . All received diet and lifestyle counselling at inclusion and metformin 850 mg three times daily during the whole study . Main outcome measures were : and rogen levels , body mass index ( BMI ) , insulin c-peptide , fasting glucose and serum lipids . Two-tailed t-tests and Pearson 's statistics were used . RESULTS Compared with the placebo , dexamethasone  reduced testosterone by 27 % , and rostenedione by 21 % , dehydroepi and rosterone sulphate by 46 % and free testosterone index by 50 % in women with PCOS treated with diet and lifestyle advice , and metformin .  BMI , fasting glucose , insulin c-peptide and serum lipid levels were unaffected . CONCLUSIONS Six-month , low-dose dexamethasone treatment further reduces and rogen levels in metformin-treated PCOS women This study was conducted to evaluate the efficacy of metformin compared with ovarian drilling in the treatment of clomiphene citrate ( CC ) resistant women with polycystic ovary syndrome . A total of 161 infertile , CC-resistant women with PCOS aged 22 - 34 years ( mean 25.5 ± 4.4 ) were evaluated prospect ively during the period between January 2000 and December 2001 . Patients were allocated into two groups ; group 1 includes 64 women who received metformin , 850 mg twice daily throughout the cycle , and group 2 which includes  97 women who underwent laparoscopic ovarian drilling .  If spontaneous ovulation or pregnancy was not achieved within 3 months after treatment , CC was added with increments of 50 mg ( up to 150 mg/day ) for both groups . Clinical and menstrual characteristics in addition to the hormonal profile were evaluated before and after the treatment . There were no significant differences between the two groups in terms of age , body weight , BMI , duration of infertility and serum hormone levels ( and rogens , gonadotrophins , insulin ) before starting the treatment . A significant improvement in the regularity of menstrual cycles ( P<0.05 ) and a significant reduction in the serum levels of testosterone ( P<0.01 ) , and rostenedione ( P<0.01 ) , DHEAS ( P<0.05 ) , LH ( P<0.01 ) and LH : FSH ratio ( P<0.05 ) were noted after the treatment . There were no significant differences between the metformin group compared with the drilling group in the rates of ovulation ( 79.7 % vs. 83.5 % ) and pregnancy ( 64.1 % vs. 59.8 % ) . It is concluded that CC-resistant patients with polycystic ovary syndrome can be treated effectively either by metformin or by laparoscopic ovarian drilling . Menstrual cycle pattern and the rates of ovulation and pregnancy are improved significantly , due most probably to the significant decrease in the levels of and rogens and luteinising hormone Purpose of review The purpose of this review is to provide a critical summary of recent studies on the clinical effects of metformin in polycystic ovary syndrome . Recent findings After the recognition that hyperinsulinaemia is a fundamental disturbance in polycystic ovary syndrome , a novel and promising form of therapy in the form of insulin-sensitizing drugs has been introduced . Among these , metformin is the most widely used . This therapeutic intervention has been shown to exert beneficial effects on the endocrine and metabolic disturbances that characterize the syndrome and , more recently , to improve the reproductive outcome in women with polycystic ovary syndrome . With rapid progress in this area , metformin use has also been extended to the management of lean polycystic ovary syndrome patients . Summary Although most studies are nonr and omized trials , current data provide a rationale for metformin as first-line management for women with polycystic ovary syndrome , alone or in combination with conventional treatments . Controversy still exists , however , regarding the mechanisms by which metformin exerts its beneficial effects in polycystic ovary syndrome Polycystic ovarian syndrome ( PCOS ) is one of the most common endocrine diseases in women . This syndrome is characterized by hyper and rogenism , chronic anovulation , infertility and obesity . The association between PCOS-related hyper and rogenemia and insulin resistance is well documented in the literature . Insulin resistance and the result ing raised plasma levels of insulin are reported to be responsible for the high and rogen concentration observed in patients with PCOS . In this prospect i ve study , blood sample s for levels of testosterone ( T ) , dehydroepi and rosterone sulfate ( DHEAS ) , luteinizing hormone ( LH ) , follicle-stimulating hormone ( FSH ) , LH/FSH , prolactin and fasting blood sugar ( FBS ) before starting metformin administration were obtained r and omly from 40 women who were apparently obese , had PCOS and had been referred to a university hospital .  Metformin was then given at a dose of 500 mg three times a day for 8 weeks , after which time the pretreatment study was repeated . Clinical symptoms of PCOS , including acne and hirsutism score and body mass index ( BMI ) , were assessed before and after the treatment cycle . Metformin therapy result ed in a significant decrease in total testosterone levels and FBS . There was also a significant decline in BMI , length of the menstrual cycle , acne and hirsutism score . There were no significant changes in the levels of DHEAS , prolactin , FSH or LH , or in LH/FSH . The effect of metformin on subjects with elevated DHEAS levels was different to that on individuals with normal DHEAS levels . In the latter group there were only significant improvements in the length of the menstrual cycle , BMI and testosterone and DHEAS levels . It is concluded that metformin therapy in subjects with PCOS results in a decrease in fasting blood sugar and testosterone levels , and leads to a significant improvement in the clinical manifestation of hyper and rogenism . These responses also related to the level of adrenal function OBJECTIVE To assess the effects of 6 months of metformin therapy on clinical and biochemical parameters in polycystic ovary syndrome ( PCOS ) and to evaluate those parameters in responders and nonresponders to identify the subjects who respond to an insulin sensitizer in PCOS . STUDY DESIGN Sixty-six diagnosed PCOS patients were recruited . Baseline characteristics ( menstrual history , hirsutism scoring , acne grading , body mass index [ BMI ] , serum luteinizing hormone and follicule-stimulating hormone [ LH/FSH ] ratio , testosterone , fasting insulin and glucose/insulin index ) were assessed initially and 6 months after metformin therapy . Three groups were constructed on the basis of menstrual symptoms : oligomenorrhea ( group I ) , amenorrhea ( group II ) and hypomenorrhea ( group III ) . Responders were those who had improvements in menstrual pattern or conceived . Response was compared in 3 groups , and biochemical parameters were compared in responders and nonresponders . RESULTS There were 44 ( 66.6 % ) oligomenorrheic , 17 ( 25.7 % ) amenorrheic and 5 ( 7.5 % ) hypomenorrheic cases and 31 ( 46.5 % ) infertile women . In total , 85.7 % responded to treatment ; the rest ( 14.3 % ) were nonresponders . Among responders , 62.29 % achieved regular periods , 22.95 % experienced improvements in their menstrual abnormalities , and 13 % conceived . Overall , a significant reduction occurred in BMI ( P = .04 ) , mean testosterone ( P = .03 ) and mean fasting insulin levels ( P = .01 ) , but no significant improvement was observed in hirsutism , acne , LH/FSH ratio or glucose/insulin index . A total of 9.75 % , 18.75 % and 30 % did not respond in the oligomenorrheic , amenorrheic and hypomenorrheic groups , respectively ( P = .04 ) . Testosterone and insulin were reduced significantly in responders ( P = .05 and .01 , respectively ) but not in nonresponders ( P = .26 and .73 ) . An initial high LH/FSH ratio and lower testosterone levels were associated with a better response . CONCLUSION Six months of metformin therapy improved menstrual cyclicity and fertility in women with PCOS . It result ed in a decline in testosterone and insulin levels . Oligomenorrheic patients with an increased LH/FSH ratio and lower testosterone levels responded better Low- grade chronic inflammation , reflected in elevated levels of serum C-reactive protein ( CRP ) , has recently been linked to obesity , insulin resistance syndromes such as polycystic ovary syndrome ( PCOS ) , and an increased risk of cardiovascular disease . Because the insulin sensitizer metformin has been shown to improve metabolic disturbances in PCOS , it was of particular interest to examine serum CRP levels during metformin therapy .  Twenty nonobese women [ body mass index ( BMI ) < /= 25 kg/m(2 ) ] and 32 obese women ( BMI > /== " BORDER="0 " > 27 kg/m(2 ) ) with PCOS were r and omized to receive either metformin ( 500 mg twice daily for 3 months , then 1000 mg twice daily for 3 months ) or ethinyl estradiol ( 35 micro g)-cyproterone acetate ( 2 mg ) oral contraceptive pills . The serum concentrations of CRP were significantly higher in obese than in nonobese subjects at baseline [ 4.08 + /- 0.53 ( SE ) vs. 1.31 + /- 0.28 mg/liter ; P < 0.001 ] and correlated to BMI and to a lesser extent waist-hip ratio , suggesting that the elevated CRP levels may be related to obesity and not only to PCOS itself . During metformin treatment , serum CRP levels decreased significantly from 3.08 + /- 0.7 mg/liter to 1.52 + /- 0.26 mg/liter at 6 months in the whole study population ( P = 0.006 ) and especially in obese subjects . In contrast , the treatment with ethinyl estradiol-cyproterone acetate increased serum CRP levels from 2.91 + /- 0.68 mg/liter to 4.58 + /- 0.84 mg/liter ( P < 0.001 ) . Whether this effect is related to estrogen action in the liver or whether it reflects increased inflammation process and possible risks for cardiovascular disease remains unclear . The decrease of serum CRP levels during metformin therapy is in accordance with the known beneficial metabolic effects of this drug and suggests that CRP or other inflammation parameters could be used as markers of treatment efficiency in women with PCOS BACKGROUND AND OBJECTIVE Polycystic ovary syndrome ( PCOS ) , with an incidence of 5 % in women of reproductive age , is defined as the presence of oligo- or amenorrhea in combination with hyper and rogenism . Most patients also suffer from impaired insulin action ( insulin resistance ) . PCOS thus resembles the metabolic syndrome ( type 2 diabetes mellitus , hypertension , lipid disorders , atherosclerosis ) . International studies showed a beneficial effect of metformin treatment on biochemical and reproductive parameters in PCOS . The aim of our study is the evaluation of metformin treatment in a German PCOS sample . PATIENTS AND METHODS 103 PCOS women ( age 18 - 40 ) were treated , according to their body weight , with either 1000 mg or 1700 mg metformin per day after assessment of insulin resistance . Clinical features as well as endocrine and metabolic parameters were recorded at baseline and at 1 , 6 , and 12 months of treatment . Additionally , baseline data were compared with those of 98 control subjects ( age 18 - 38 ) . RESULTS PCOS women showed significantly higher body mass index , body fat mass and and rogen levels , as well as an impaired glucose- and insulin metabolism compared to controls . Metformin treatment ameliorated acne ( 36 % to 4 % ) , hirsutism-score ( 11.2 to 9.7 ) and restarted normal menstrual cycles in 66.7 % of PCOS-women . Sixteen of 48 patients with unfulfilled wish to conceive became pregnant during therapy . Metformin  restored menses in all previously amenorrheic women . Comparing post-metformin versus baseline levels , HOMA-IR ( 4.6 to 2.3 ) , AUC-I ( 379 to 225 ) and 2-h glucose ( 117 to 90 mg/dl ) decreased significantly . Furthermore , metformin decreased testosterone ( 2.9 to 1.8 nmol/l ) , free and rogen index ( 9.1 to 5.3 ) and dehydroepi and rosterone levels ( 5.1 to 3.9 mg/l ) . CONCLUSION Metformin improves significantly hyper and rogenism and insulin resistance in PCOS patients and appears to be an efficacious mode of therapy Metformin effectively restores insulin sensitivity in insulin-resistant women with polycystic ovary syndrome ( PCOS ) . We examined whether metformin , given prior to and during ovarian stimulation for in vitro fertilization ( IVF ) , altered follicle stimulating hormone ( FSH ) requirement and increased the number of collected oocytes in these women . Seventeen insulin-resistant women with PCOS were recruited to our IVF unit to receive two consecutive cycles of ovarian stimulation with or without metformin co-treatment , the order of treatments being r and omized using a table of r and om numbers . Metformin treatment ( 1500 mg/day ) started 3 weeks before downregulation with buserelin acetate and was continued throughout ovarian stimulation with human recombinant FSH .  Nine women completed both cycles , the results of eight women being excluded because of pregnancy after the first cycle ( n = 4 ) or because the protocol of the study was not followed ( n = 4 ) . Mean total FSH dose was 2301 IU ( range 1500 - 6563 IU ) in metformin cycles and 2174 IU ( range 1200 - 3900 IU ) in parallel control cycles , while the mean number of collected oocytes was 8.6 ( range 2 - 28 ) and 4.6 ( range 1 - 16 ) , respectively . Bayesian analysis showed probabilities of 0.05 that metformin  reduces FSH requirement by at least 10 % , and of 0.61 that at least 10 % more oocytes are collected after metformin co-treatment . Co-administration of metformin is therefore likely to increase the number of oocytes collected after ovarian stimulation in insulin-resistant women with PCOS but is unlikely to reduce the requirement for FSH OBJECTIVE In women suffering from polycystic ovary syndrome ( PCOS ) , correction of hyperinsulinemia results enhances spontaneous ovulation or alternatively , the responsiveness to ovulation induction agents such as clomiphene citrate ( CC ) . We investigated the effect of rosiglitazone maleate on ovulation induction in overweight and obese , CC-resistant women with PCOS . DESIGN Double-blind , r and omized , placebo-controlled trial . SETTING Academic reproductive endocrinology clinic . PATIENT(S ) Overweight and obese women with clinical and laboratory manifestations of PCOS who desired pregnancy and were resistant to CC . INTERVENTION(S ) Twenty-five women were r and omized into two treatment groups . Subjects in Group I ( n = 12 ) were r and omized to receive rosiglitazone 4 mg b.i.d . with a placebo on cycle days 5 - 9 . Group II ( n = 13 ) was r and omized to receive rosiglitazone 4 mg b.i.d . with CC on cycle days 5 - 9 . The duration of the study was 2 months . MAIN OUTCOME MEASURE(S ) The primary outcome was ovulation as defined by luteal serum progesterone greater than 5 ng/dL assessed on days 21 , 24 , and 28 of the cycle . Secondary outcomes were pregnancy and changes in insulin sensitivity , serum lipoproteins , and and rogens . RESULT ( S ) Overall , 14 of 25 ( 56 % ) women , who were previously resistant to CC , successfully ovulated . In subjects taking rosiglitazone alone ( Group I ) , 4 of 12 ( 33 % ) subjects ovulated compared with 10 of 13 ( 77 % ) women r and omized to rosiglitazone with CC ( Group II ) ( P=.04 , Fisher 's exact ) . One subject in Group I became pregnant , result ing in one uncomplicated live birth ; two subjects in Group II conceived , with one successful live birth and one first trimester , spontaneous abortion . For all subjects , fasting insulin declined from 29.4 + /- 13.8 microU/mL to 17.3 + /- 7.8 microU/mL after rosiglitazone ( P=.003 , paired t-test ) . Although mean levels of total testosterone ( T ) and dehydroepi and rosterone sulfate ( DHEAS ) did not decline significantly , sex hormone-binding globulin ( SHBG ) did increase from 0.7 + /- 0.3 microg/dL to 1.0 + /- 0.3 microg/dL after rosiglitazone therapy ( P=.001 , paired t test ) . There was also a decrease in luteinizing hormone ( LH ) from 9.4 + /- 6.3 mU/mL to 7.2 + /- 3.7 mU/mL ( P=.01 ) . Lipoproteins including total cholesterol , low-density lipoprotein ( LDL ) , high-density lipoprotein ( HDL ) , and triglycerides did not change . CONCLUSIONS Short-term rosiglitazone therapy enhances both spontaneous and clomiphene-induced ovulation in overweight and obese women with PCOS .  Rosiglitazone therapy improves insulin sensitivity and decreases hyper and rogenemia primarily through increases in SHBG Abstract Objective . To examine the effect of metformin therapy on ovarian response in clomiphene-resistant PCOS patients . Design . R and omized prospect i ve study . Setting . Zeynep Kamil Hospital IVF Center . Patients . Thirty-two female PCOS patients with clomiphene citrate resistance . Interventions . Test group A received 2 × 850 mg/day metformin therapy for 8 weeks , followed by gonadotropin induction . Only gonadotropin induction was applied to Control group B.Main outcome measures . Total gonadotropin dosage , duration of gonadotropin therapy , estradiol level on HCG-day , number of follicles with ≥16 mm diameter , number of cases with hyperstimulation development , number of cancelled cycles , endometrial thickness on HCG-day , pregnancy outcome , multiple pregnancy rate . Results . The total gonadotropin doses given to metformin- study group was significantly lower than the control group . In addition , duration of therapy , HCG level , plasma estradiol level on HCG-day in the study group was significantly lower than in the control group . Conclusions . Metformin therapy has led to a higher pregnancy outcome , as well as to a decrease in hyperstimulation risk , cycle cancellations , and multiple pregnancy rates with a lower gonadotropin dosage Polycystic ovary syndrome ( PCOS ) is a common endocrine condition in women of reproductive age associated with obesity . It may involve dysregulation of ghrelin , a hormone implicated in appetite regulation . The effect of diet composition on ghrelin is unclear . Overweight women with and without PCOS were r and omized to a high-protein ( 40 % carbohydrate , 30 % protein ; 10 PCOS , six non-PCOS ) or st and ard protein diet ( 55 % carbohydrate , 15 % protein ; 10 PCOS , six non-PCOS ) for 12 wk of energy restriction and 4 wk of weight maintenance . Diet composition had no effect on fasting or postpr and ial ghrelin or measures of satiety .  Non-PCOS subjects had a 70 % higher fasting baseline ghrelin ( P = 0.011 ) , greater increase in fasting ghrelin ( 57.5 vs. 34.0 % , P = 0.033 ) , and greater maximal decrease in postpr and ial ghrelin after weight loss ( -144.1 + /- 58.4 vs. -28.9 + /- 14.2 pg/ml , P = 0.02 ) than subjects with PCOS . Subjects with PCOS were less satiated ( P = 0.001 ) and more hungry ( P = 0.007 ) after a test meal at wk 0 and 16 than subjects without PCOS . Appetite regulation , as measured by subjective short-term hunger and satiety and ghrelin homeostasis , may be impaired in PCOS OBJECTIVE To evaluate the effects of metformin administration on spontaneous LH episodic release in a group of nonobese polycystic ovary ( PCOS ) patients . DESIGN Controlled clinical study . SETTING PCOS patients in a clinical research environment . PATIENT(S ) Twenty nonobese PCOS patients were enrolled after informed consent . INTERVENTION(S ) All patients underwent hormonal evaluations and a pulsatility study ( sampling every 10 minutes for 4 hours ) before and at the sixth month of therapy ( metformin , 500 mg , p.o . b.i.d . ) . Ultrasound examinations and Ferriman-Gallwey scoring were also performed . MAIN OUTCOME MEASURE(S ) Measurements of plasma LH , FSH , estradiol ( E(2 ) ) , and rostenedione ( A ) , 17-hydroxy-progesterone ( 17-OHP ) , and testosterone ( T ) , glucose , insulin , and C-peptide concentrations . RESULT ( S ) After 6 months of metformin administration , the plasma LH , 17-OHP , A , and T levels and LH/FSH ratio were significantly reduced . Insulin sensitivity , expressed as the glucose-to-insulin ratio , was significantly improved under glucose load after 6 months of treatment . Spontaneous LH episodic release showed a significant reduction in pulse amplitude with no changes in pulse frequency . Menstrual cyclicity was restored in all amenorrheic and oligomenorrheic women . The ovarian volume and Ferriman-Gallwey scores also were significantly reduced . CONCLUSION ( S ) Metformin administration improves reproductive axis functioning in hyper and rogenic nonobese PCOS patients . By acting on the ovary and restoring normal ovarian activity , metformin positively modulates the reproductive axis ( namely GnRH-LH episodic release ) We compared the efficacy of spironolactone ( 50 mg/d ) with metformin ( 1000 mg/d ) after r and om allocation in 82 adolescent and young women with polycystic ovary syndrome ( PCOS ) on body mass index ( BMI ) , waist-to-hip ratio , blood pressure , menstrual cyclicity , hirsutism , hormonal levels , glycemia , and insulin sensitivity at baseline and at the 3rd and 6th months of treatment . Sixty-nine women who completed the follow-up had a mean age of 22.6 + /- 5.0 yr and mean BMI of 26.8 + /- 4.0 kg/m2 . The number of menstrual cycles in the spironolactone and metformin groups increased from 6.6 + /- 2.1 and 5.7 + /- 2.3 at baseline to 9.0 + /- 1.9 and 7.4 + /- 2.6 at 3rd month and to 10.2 + /- 1.9 and 9.1 + /- 2.0/ year at the 6th month ( P = 0.0037 ) , respectively . The hirsutism score decreased from 12.9 + /- 3.2 and 12.5 + /- 4.9 at baseline to 10.1 + /- 3.1 and 11.4 + /- 4.1 at the 3rd month and to 8.7 + /- 1.9 and 10.0 + /- 3.3 at the 6th month , respectively . Both groups showed improvement in glucose tolerance and insulin sensitivity , although the metformin effect was significant in the latter . Serum LH/FSH and testosterone decreased in both groups . BMI , waist-to-hip ratio , and blood pressure did not change with either drug . We conclude that both drugs are effective in the management of PCOS .  Spironolactone appears better than metformin in the treatment of hirsutism , menstrual cycle frequency , and hormonal derangements and is associated with fewer adverse events
PURPOSE OF REVIEW Metformin has become an established treatment for women with polycystic ovary syndrome , although controversy remains as to how effective it is and in which population s it should be used .
This review examines the recent literature in order to ascertain the evidence for the benefits and disadvantages of using metformin in women with polycystic ovary syndrome .