polycystic ovary syndrome ( pcos ) is a heterogeneous and complex endocrine disorder associated with hyperandrogenism and insulin resistance signs and symptoms such as obesity , abnormal glucose tolerance test or type 2 diabetes , abnormal blood lipid profile , high blood pressure and cardiovascular disease ( 1 ) .
this disorder is prevalent and affects 5 - 10% of women of reproductive age ( 2 ) and causes infertility in 75% of these women due to chronic anovulation ( 3 ) .
many drugs were used as a treatment for pcos or control its consequences , including metformin ( 4 ) , simvastatin ( 5 ) , atorvastatin ( 6 ) , n - acetyl - cysteine ( nac ) ( 7 ) and flutamide ( 8) . in general , all of these drugs have positive effects in improving hyperandrogenic symptoms and regulation of menstrual cycles , but simvastatin and metformin have been more commonly used than others for treatment and research purposes . in one study , long - term treatment with simvastatin was more effective than metformin for control of hyperandrogenism sign and increased menstrual regulation in women with pco ( 9 ) .
there are several published studies regarding the effectiveness of statins administration in women with pco ( 10 , 11 ) , but in comparison with metformin there is no published research about drug administration before or during icsi cycle .
simvastatin a drug from statins group , inhibits hmg - coa reductase and reduces cholesterol production , increases liver ldl receptor sensitivity and hdl level , meanwhile decreases tg level in blood circulation ( 12 ) .
moreover , statins prevent theca - interstitial cell proliferation in ovaries and therefore reduce total androgen production ( 13 ) .
metformin as a biguanid drug , blocks glucose synthesis in liver and enhances peripheral sensitivity to insulin , which finally decreases androgen level in patients with pco and enhances the chance of pregnancy ( 14 ) . according to latest cochrane published study about metformin treatment before and during icsi cycle , live birth or pregnancy rate
was not improved ( 15 ) ; the cochrane database announced that although simvastatin improved lipid profile and hyperandrogenism sign , it had no significant effect on pregnancy chance ( 16 ) , of course in natural cycle .
we decided to compare the efficacy of both drugs as a pretreatment regiment before icsi cycle in patients with pco .
in this prospective , double blind , randomized clinical trial , 40 women with pcos and a history of infertility referring for first icsi cycle to imam khomeini hospital affiliated with ahvaz jundishapur university of medical sciences ( ajums ) were selected based on closed enveloped randomization method from december 2010 to november 2012 to receive simvastatin ( group a ) or metformin ( group b ) . according to the variance of previous studies ,
the sample size was calculated as 20 patients for each group . in accordance with the guidelines of the declaration of helsinki , after approval of university ethical committee ( eth-3251 ) ,
the study was submitted on iranian health ministry website for clinical trials ( www.irrct.ir ) .
pcos considered as presence of two of the following criteria including menstrual irregularities ( oligomenorrhea or amenorrhea ) , clinical and laboratory findings of hyperandrogenism and polycystic ovaries on ultrasound evaluation . besides , inclusion criteria were aged 20 - 35 years , a history of infertility for at least two years ( either primary or secondary ) , normal tsh and prolactin and candidates for the first cycle of icsi .
patients with other causes of infertility , including tubal factors , endometriosis and male factor infertility were excluded .
patients who used metformin , lipid control drugs , clomiphene , letrozole or doing iui ( intrauterine insemination ) in the past 3-months before study or having medical problems such as kidney or liver diseases , diabetes or a history of elevated blood lipids were excluded .
body mass index ( bmi ) and the score of hirsutism were assessed according to the ferriman  gallwey scoring system ( figure 1 ) . in this system ,
hair growth in a male pattern on a woman shown in four different degrees of severity in 11 different body parts , namely the upper lip , chin , chest , upper back , lower back , upper abdomen , lower abdomen , arm , forearm , thigh and lower leg ( 17 ) . on the third day of menstruation ,
all patients were evaluated for total testosterone , lh , fsh , tg , total cholesterol , ldl , hdl , fbs , gtt with 75 grams glucose ( blood sugar measured one and two hours after drinking it ) , prolactin and tsh . after getting the first blood sample for biochemical evaluation , in group
a , patients received simvastatin 20 mg daily ( osvah pharmaceutical company , iran ) plus low dose oral contraceptive pill ( ocp ) daily for eight weeks . in group b
, patients received metformin 500 mg tds ( osvah pharmaceutical company , iran ) plus low dose ocp daily for eight weeks .
then , all patients were again evaluated for previous biochemical parameters ( except prolactin and tsh ) and bmi measurement and hirsutism scoring .
patients were enrolled in the icsi protocol according to the long protocol ; from the day of twenty - one of the second cycle , subcutaneous superfact ( 0.5 mg daily , triptrolein , hoechst , frankfort , germany ) injection was started .
after menstruation on the third day of cycle , both drugs ( simvastatin and metformin ) were discontinued and after vaginal sonography control and reducing superfact to 0.25 mg daily , induction of ovulation with folliotropin alfa ( gonal - f , merck , serono .
ovarian response was examined by transvaginal sonography six days later and gonal - f dosage adjusted according to the patient response ; when at least three follicles with a size of 18 mm detected , human chorionic gonadotropin ( hcg ) 10000 units ( profasi .
switzerland ) was injected intramuscularly and ovarian puncture was performed 36 - 40 hours later . after ovarian puncture , the number of mii oocytes and after sperm injection , on the day 3 , the number of embryos of grade a was recorded .
the incidence of ovarian hyperstimulation syndrome ( ohss ) was reported in the both groups .
then , support of luteal phase was started with vaginal suppository of micronized progesterone 400 mg twice daily .
the first ultrasound was performed five weeks after embryo transfer in cases of pregnancy positive test .
cases of abortion , ectopic pregnancy ( ep ) , ongoing pregnancy ( passing 14 weeks of gestational age ) and negative pregnancy were detected .  
student s t - test for unpaired data and sample t - test for paired information were used .
also chi - square and fisher s tests were used to assess frequency distribution and clinical outcome .
regression and anova tests were used for comparison between the groups . for gtt result interpretation ,
p value < 0.05 was considered as significant and the power of study was 80% .
75% of patients in group a , were obese ( bmi > 30 kg / m ) and in group b , 65% .
after eight weeks treatment in both groups , reduction of mean hirsutism score was significant , although it was more meaningful in simvastatin group ( table 2 ) ; this reduction in mean bmi level was not significant ( table 3 ) .
biochemical parameters before the treatment in the both groups were not different ( table 4 ) .
after eight weeks in group a receiving simvastatin , testosterone , fsh , lh , cholesterol ( chol ) and ldl significantly decreased ; meanwhile hdl level elevated . in group b , after metformin administration the level of fsh , testosterone , tg and chol reduced meaningfully ( table 5 ) .
the mean values of three blood sugar measurements ( fbs/1 hour/2 hours ) before starting the treatment were not different between the two groups ( group a : 12208  1658.03 mg / dl vs. group b , 12302  1789.87
after the treatment , roc showed improvement area under curve ( auc ) in glucose tolerance test in the both groups ; although there were no significant differences between the two groups ( p value 0.11 ) ( figure 2 ) .
a , before the treatment in metformin ; and c , simvastatin ; b , after the treatment in metformin ; and d , simvastatin . after ovarian puncture , the number of oocytes in phase2 meiosis ( m2 ) in simvastatin treated group was 1.35  1.6 , and in metformin treated group 2  3.87 ( p value 0.48 ) . on the third day after ovarian puncture ,
the number of grade a embryos in group a was 1.2  1.3 versus 1.1  1.4 in group b ( p value 0.79 ) , which was not significantly different . in the both groups
the pregnancy rate in group a was six cases ( 30% ) ongoing and seven cases in group b ( 35% ) .
to the best of our knowledge , this is the first published study comparing simvastatin and metformin as a pretreatment regiment for icsi cycle in pcos women and there is one study regarding the effectiveness of simvastatin before ivf ( 18 ) .
women with pcos have enlarged ovaries with an increased number of small follicles with more theca cells , which are androgen - producing cells .
it is also clear that theca cells of women with pcos produce higher amount of androgens compared with the theca cells of normal women .
increased expression of genes involved in androgen production , such as cyp11a and cyp17 has been observed in these cells ( 9 ) .
metformin - induced reduction in testosterone is not only because of decreasing size of the ovarian theca cells , but also due to the direct action of metformin .
studies have shown that metformin inhibits the production of testosterone and androstenedione in the cultured theca cells .
metformin also decreased expression of steroidogenic acute regulatory ( star ) protein and 17-hydroxylase/17 , 20-desmolase ( cyp17 ) ( 19 ) .
studies have shown that statins reduce cell proliferation , increase apoptosis and inhibit producing testosterone in humans and rat theca cells ( 10 , 13 ) .
the positive effects of simvastatin in reducing hirsutism and testosterone have been confirmed by other researchers ( 5 ) ; this reduction in testosterone level , but not the hirsutism score after metformin administration has been reported , but in our study bmi decreased after six months therapy ( 20 ) . in another study , after six months of treatment , simvastatin improved hyperandrogenism parameters like total testosterone , hirsutism score , total cholesterol , ldl and bmi better than metformin ( 9 ) .
lipid profile analysis showed that simvastatin significantly reduced ldl and total cholesterol , and increased hdl .
this effect reflects direct competitive prevention of the controlling step of cholesterol production by inhibiting 3-hydroxy3methylglutaryl coenzyme a reductase ( 21 ) .
however , metformin significantly decreased triglyceride and ldl by its anti - lipolytic effects , reducing circulating free fatty acid concentrations and therefor the level of triglycerides ( 22 , 23 ) , although this reduction in ldl level in our study was not significant .
in the present study , lh and fsh hormones were significantly lower in simvastatin group after treatment , but in the metformin group only fsh concentrations decreased . in women with pco , reduction in fsh level reflects decreased gnrh frequency secretion due to reduction of hypothalamic dopamine and opioid production and from negative feedback of chronically elevated estrone concentration ( increased peripheral aromatization of elevated androstenedione ) and decreased progesterone level ( chronic anovulation ) ( 24 ) .
in contrast to fsh , abnormal lh production is due to increased pulse amplitude and frequency secondary to altered pulsatile gnrh secretion ; this elevated lh led to ovarian hyperandrogenism ( 25 ) .
metformin directly affected gonadotropin - secreting cells and reduced lh production and elevated fsh level by regulating fsh gene expression ( 26 ) .
simvastatin could reduce lh level , but had no effect on fsh ( 11 ) ; this impressive effect for normalized gonadotropins level improved in other study ( 27 ) .
simvastatin reduced lh level by decreasing ovarian testosterone production secondary to inhibition of theca - interstitial proliferation . in our study ,
reduction in lh level was seen in the both groups , although it was more significant in group a ; we could not find any explanation about reduced level of fsh in the both groups . in conclusion
, according to only published study about simvastatin administration before ivf cycle ( 18 ) and in agreement with cochrane review about co - administration of metformin and icsi cycle ( 15 ) , the outcome of icsi cycle does not progress significantly , but biochemical parameters , signs and symptom in women with pco improved . these drugs as a pretreatment protocol before icsi cycle could alter the results of cycle if used in more patients , or in longer or higher doses .
 background : drugs administration as a pretreatment regiment before icsi cycle in pcos patients could enhance the success rate.objectives:the aim of this study was to compare the effectiveness of metformin with simvastatin in patients with polycystic ovary syndrome ( pcos ) candidates for intra - cytoplasmic sperm injection ( icsi ) before starting the cycle.patients and methods : in this prospective , double blind , randomized clinical trial the efficacy of these drugs was evaluated in 40 women with pco syndrome ( 20 patients in each group ; a : simvastatin and b : metformin ) candidates for icsi . in the both groups , metformin and simvastatin administrated for eight weeks before starting the icsi cycle . 
 endocrine , metabolic and clinical parameters were measured before and after drug therapy ; also , the results of icsi cycle evaluated in the both groups.results:both drugs improved hirsutism score significantly , but simvastatin better than metformin ( group a , 24.5  3.6 p : 0.0001 vs group b , 22.9  5.9 p : 0.003 ) . 
 the reduction in body mass index ( bmi ) was not significant in the groups . 
 simvastatin reduced some biochemical parameters such as fsh , lh , testosterone , total cholesterol , ldl and increased hdl level significantly , whereas metformin decreased fsh , tg , testosterone and total cholesterol significantly . 
 overall , respectively 35% and 30% of patients treated with metformin and simvastatin became pregnant . 
 there was no significant difference between the effects of these two drugs on icsi cycle results like oocyte in meiosis2 ( m2 ) phase ( 1.35  1.6 vs. 2  3.87 , p value : 0.4 ) and the number of grade a , embryo ( 1.2  1.3 vs. 1.1  1.4 , p value : 0.7).conclusions : simvastatin effectively improved hyperandrogenism signs and symptoms in patients with pco , but this effect as a pretreatment regiment was not more expressive than metformin in icsi cycle outcome . 
1. Background
2. Objectives
3. Patients and Methods
4. Results
5. Discussion