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1.  Effect of Metformin on Serum Ferritin Level in Women with Polycystic Ovary Syndrome 
Polycystic ovary syndrome (PCOS) is one of the most common diseases among women associat-ed with various inflammatory reactants such as C-reactive protein (CRP) and ferritin. This study aimed to investi-gate the effect of metformin on probable reduction of serum ferritin in patients with PCOS.
This study was conducted on 45 patients with PCOS who had not other systemic diseases and did not take any medications. Weight, waist and hip circumstances (WHR), body mass index (BMI), metabolic indexes, CRP, ferritin and “Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) ˝ were measured before the study. Metformin (500 mg/tid) tablets were prescribed for three months and then same above parameters were re-measured.
Of 45 patients, 19 (42.2%) were overweight and 14 (31.1%) were obese. After drug therapy, there was a significant reduction in waist circumstance and serum ferritin. This reduction was significant only in the lean and overweight groups but not in the obese group. There was not significant association between serum ferritin and CRP, HOMA-IR, BMI and WHR. There was not significant correlation between CRP and HOMA-IR and also BMI.
The effect of metformin on reduction of serum ferritin was not significant just in obese group and was not associated with metabolic and anthropometric indexes.
PMCID: PMC3371989  PMID: 22737516
Ferritin; Polycystic Ovary Syndrome; Metformin
2.  Effects of insulin-sensitizing agents and insulin resistance in women with polycystic ovary syndrome 
The aim of this study was to investigate the effect of insulin sensitizing agents on hormonal and metabolic parameters as well as menstrual patterns in women with polycystic ovary syndrome (PCOS).
One hundred and twenty-three patients with PCOS were included. Metformin was administered to patients at 1,500 mg or 1,700 mg daily for 3 months. If the patients had no improvement of the menstrual cycle or metformin-related adverse effects developed, the patients changed medication to a daily dose of either 15 mg pioglitazone or up to 45 mg. Then resumption of a regular menstrual cycle or recovery of ovulation was evaluated. Hormonal and metabolic profiles were compared between the response and non-response group to insulin sensitizing agents.
One hundred and five patients with PCOS were treated with metformin for 3 months. Forty-eight patients (45.7%) showed improvement of menstrual cycle regularity after 3 months of metformin use, whereas 57 patients (54.3%) had no change. The mean free testosterone measured after 3 months of treatment was significantly lower in metformin responders than in non-responders. The other parameters did not differ between the groups. Of the 23 patients who used pioglitazone for 3 to 6 months, 19 patients (82.6%) showed improvement in their menstrual cycles.
Metformin treatment seems to be effective for the improvement of menstrual cyclicity irrespective of insulin resistance in women with PCOS. When metformin related adverse effect occurred, pioglitazone would be effective for aiding the resumption of the menstrual cycle.
PMCID: PMC3714427  PMID: 23875167
Polycystic ovary syndrome; Metformin; Pioglitazone
3.  Use of ethinylestradiol/drospirenone combination in patients with the polycystic ovary syndrome 
Polycystic ovary syndrome (PCOS) is one of the most common endocrine/metabolic disorders found in women, affecting approximately 105 million women worldwide. It is characterized by ovulatory dysfunction, often presenting as oligomenorrhea or amenorrhea and either clinical or biochemical hyperandrogenism. Combined oral contraceptive (COC) therapy has long been a cornerstone of care for women with PCOS. COC therapy often provides clinical improvement in the areas of excessive hair growth, unpredictable menses, acne, and weight gain. One of the main issues in COC therapy is choosing the most appropriate progestin component to provide the greatest anti androgenic effects. Drospirenone, a relatively new progestin, has shown benefit in the PCOS population when used in conjunction with ethinyl estradiol. We now review the role of COCs in PCOS, focusing specifically on drospirenone. Controversy over metabolic effects of COCs in PCOS is also discussed.
PMCID: PMC2504056  PMID: 18728832
polycystic ovary syndrome; PCOS; oral contraceptives; drospirenone; treatment
4.  Effects of Metformin With or Without Supplementation With Folate on Homocysteine Levels and Vascular Endothelium of Women With Polycystic Ovary Syndrome 
Diabetes Care  2009;33(2):246-251.
To evaluate whether the administration of metformin exerts any effects on serum homocysteine (Hcy) levels in patients with polycystic ovary syndrome (PCOS) and whether supplementation with folate enhances the positive effects of metformin on the structure and function of the vascular endothelium.
A total of 50 patients affected by PCOS, without additional metabolic or cardiovascular diseases, were enrolled in a prospective nonrandomized placebo-controlled double-blind clinical study. They were grouped into two treatment arms that were matched for age and BMI. Patients were treated with a 6-month course of metformin (1,700 mg daily) plus folic acid (400 μg daily; experimental group, n = 25) or placebo (control group, n = 25). Complete hormonal and metabolic patterns, serum Hcy, folate, vitamin B12, endothelin-1 levels, brachial artery diameter at the baseline (BAD-B) and after reactive hyperemia (BAD-RH), flow-mediated dilation, and intima-media thickness in both common carotid arteries were evaluated.
After treatment, a significant increase in serum Hcy levels was observed in the control group compared with the baseline values and the experimental group. A beneficial effect was observed in the concentrations of BAD-B, BAD-RH, flow-mediated dilation, intima-media thickness, and serum endothelin-1 in both groups. However, the results were improved more significantly in the experimental group than in the control subjects.
Metformin exerts a slight but significant deleterious effect on serum Hcy levels in patients with PCOS, and supplementation with folate is useful to increase the beneficial effect of metformin on the vascular endothelium.
PMCID: PMC2809257  PMID: 19933994
5.  Long-Term Effect of Metformin on Metabolic Parameters in the Polycystic Ovary Syndrome 
Insulin resistance is a central feature of the polycystic ovary syndrome (PCOS) and may increase cardiovascular risk. Due to insulin resistance, the metabolic syndrome is more prevalent in PCOS women compared to normal women. Metformin improves the metabolic profile in PCOS in short-term studies. In this study, we evaluated the long-term effect of metformin on metabolic parameters in PCOS women during routine care without a controlled diet. We performed a retrospective medical chart review of 70 women with PCOS receiving metformin from an academic endocrine clinic. Metabolic risk factors were compared before and after metformin treatment. Time trends of these metabolic parameters were also analyzed. After a mean follow-up of 36.1 months with metformin treatment, improvements were observed for BMI (−1.09±3.48 kg/m2, p=0.0117), diastolic blood pressure (−2.69±10.35 mmHg, p=0.0378), and HDL cholesterol (+5.82±11.02 mg/dL, p<0.0001). The prevalence of metabolic syndrome decreased from 34.3% at baseline to 21.4% (p=0.0495). The course of BMI reduction during metformin treatment was significantly more pronounced in PCOS women with metabolic syndrome at baseline, compared with those without the metabolic syndrome (p=0.0369 for interaction). In conclusion, metformin improved the metabolic profile of PCOS women over 36.1 months, particularly in HDL cholesterol, diastolic blood pressure and BMI.
PMCID: PMC2907923  PMID: 20368201
Polycystic ovary syndrome; metformin; metabolic syndrome; cardiovascular risk factors
6.  Does metformin affect ovarian morphology in patients with polycystic ovary syndrome? A retrospective cross-sectional preliminary analysis 
The significance of polycystic ovarian morphology and its relation to polycystic ovary syndrome (PCOS) is unclear, but probably it is associated with higher androgen and insulin levels and lower sex hormone binding globulin (SHBG) in absence of identifiable differences in gonadotropin dynamics. The aim of this study was to evaluate ovarian morphology in patients affected by PCOS with different ovulatory responses to metformin.
In this cross-sectional analysis, we studied 20 young normal-weight PCOS patients who had received a six-month course of metformin treatment. Ten of these patients remained anovulatory (anovulatory group), whereas other ten became ovulatory, but failed to conceive (ovulatory group). Other ten age- and body mass index (BMI)-matched PCOS subjects were also enrolled as controls and observed without any treatment (control group).
After six months of metformin, in both PCOS treated groups, a similar improvement in testosterone (T) and insulin resistance indexes was observed. Moreover, in one (10.0%) and nine (90.0%) subjects from anovulatory and ovulatory PCOS groups, respectively, ovarian morphology changed, whereas a significant reduction in ovarian dimension was observed in the PCOS ovulatory group only.
PCOS patients under metformin administration demonstrate a change in ovarian morphology closely related to ovulatory response.
PMCID: PMC2694802  PMID: 19480717
7.  Anti-Műllerian hormone – a prognostic marker for metformin therapy efficiency in the treatment of women with infertility and polycystic ovary syndrome 
Journal of Medicine and Life  2012;5(4):462-464.
Background: The anti- Műllerian hormone (AMH) is secreted in women exclusively by the granulosa cells of the ovarian follicles. The serum level of AMH is a precise marker of follicle pool size. In recent clinical studies of polycystic ovary syndrome (PCOS), the serum levels of AMH were elevated about two to threefold. The use of metformin in women with infertility and PCOS has proved to be efficient: restoring ovulation and reducing metabolic dysfunctions. The aim of our study is to assess AMH as a prognostic marker for metformin therapy efficiency in the treatment of women with infertility and polycystic ovary syndrome (PCOS).
Methods: Eleven patients with infertility and PCOS were enrolled; PCOS was diagnosed according to the criteria of Androgen Excess and Polycystic Ovarian Syndrome Society 2006 (AE/PCOS). All patients have received metformin therapy. Serum AMH was recorded before and after 2 months of treatment; the normal laboratory values were 2.0-6.8 ng/ml.
Results: The primary serum AMH level of all women in study was very high: 8.99±0.99 ng/ml. After 2 months of treatment with metformin ovulation was restored in all the patients and the serum AMH levels were significantly decreased.
Conclusions: In clinical practice, serum AMH levels of women with infertility and PCOS receiving metformin are a useful predictive marker for the treatment efficiency.
PMCID: PMC3539844  PMID: 23346251
AMH; PCOS; metformin
8.  Metformin—clomiphene citrate vs. clomiphene citrate alone: Polycystic ovarian syndrome 
Polycystic ovary syndrome (PCOS) is the commonest endocrinopathy in women that is associated with reproductive and metabolic disorders.
We compared the ovulation and conception rates after the treatment with clomiphene citrate (CC) alone and in combination with metformin in infertile patients presented with polycystic ovarian syndrome (PCOS).
This randomized controlled trial of independent cases and controls was conducted at the Department of Obstetrics and Gynecology, Hera General Hospital, Makkah, Saudi Arabia from February 01 to December 31, 2008. The 42 subjects diagnosed as PCOS were divided into group A and B (21 subjects in each) for management with CC + metformin and CC alone, respectively. Group A received 500 mg three times a day of metformin continuously from the first cycle for 6 months or till pregnancy was confirmed. In both groups CC was started at a dose of 50 mg from day-2 till day-6 of the menstrual cycle. The dose of CC was increased to 100 mg in second and 150 mg in third cycle, and then remained 150 mg for the remaining three cycles. With ovulation the dose of CC was unaltered in both groups. Data were analyzed using Statistical Package for the Social Sciences (SPSS) version 16.
More than 50% females in both groups were had body mass index > 25. Group A achieved high rate of regular cycles, ovulation success, and conception than group B (71.4% vs. 38.1%; P = 0.03), (76.2% vs. 38.1%; P = 0.021), and (66.6% vs. 28.6%; P = 0.01), respectively.
Management with metformin + CC increased the ovulation and conception rates.
PMCID: PMC3713569  PMID: 23869144
Anovulation; clomiphene citrate; polycystic ovaries; metformin
9.  Efficacy of combined metformin–clomiphene citrate in comparison with clomiphene citrate alone in infertile women with polycystic ovarian syndrome (PCOS)  
Journal of Medicine and Life  2013;6(2):199-201.
Background. Polycystic ovary syndrome (PCOS) is the most common endocrinopathy in women and is associated with the reproductive and metabolic disorders.
Objectives. To compare the ovulation and conception rates after the treatment with Clomiphene Citrate (CC) alone and in combination with metformin in infertile patients presented with polycystic ovarian syndrome (PCOS).
Material & Methods. This randomized controlled trial of independent cases and controls was conducted in the Department of Obstetrics and Gynecology, Hera General Hospital, Makkah, Saudi Arabia, during 2008. The 42 subjects diagnosed as PCOS were divided into group A and B (21 subjects in each) for the management with CC + metformin and CC alone, respectively. Group A received 500mg of metformin continuously, three times a day from the first cycle, for 6 months or until the pregnancy was confirmed. In both groups, CC was started with a dose of 50 mg from day-2 until day-6 of the menstrual cycle. The dose of CC was increased to 100 mg in the second and 150 mg in the third cycle, and then 150 mg remained for the rest of three cycles. With ovulation, the dose of CC was unaltered in both groups. Data were analyzed by using SPSS version 16.
Results. More than 50% of the females in both groups had a body mass index of >25. Group A achieved a higher rate of regular cycles, ovulation success, and conception than group B (71.4% vs. 38.1%; p=0.03), (76.2% vs. 38.1%; p=0.021) and (66.6% vs. 28.6%, p=0.01), respectively.
Conclusion. Management with metformin + CC increased the ovulation and conception rates.
PMCID: PMC3725449  PMID: 23904883
Polycystic ovaries; Metformin; Clomiphene citrate; Anovulation
10.  Short-term combined treatment with liraglutide and metformin leads to significant weight loss in obese women with polycystic ovary syndrome and previous poor response to metformin 
European Journal of Endocrinology  2014;170(3):451-459.
The effect of metformin on weight reduction in polycystic ovary syndrome (PCOS) is often unsatisfactory. In this study, we investigated the potential add-on effect of treatment with the glucagon-like peptide-1 receptor agonist liraglutide on weight loss in obese nondiabetic women with PCOS who had lost <5% body weight during pretreatment with metformin.
A total of 40 obese women with PCOS, who had been pretreated with metformin for at least 6 months, participated in a 12-week open-label, prospective study. They were randomized to one of three treatment arms: metformin (MET) arm 1000 mg BID, liraglutide (LIRA) arm 1.2 mg QD s.c., or combined MET 1000 mg BID and LIRA (COMBI) 1.2 mg QD s.c. Lifestyle intervention was not actively promoted. The primary outcome was change in body weight.
Thirty six patients (aged 31.3±7.1 years, BMI 37.1±4.6 kg/m2) completed the study: 14 on MET, 11 on LIRA, and 11 on combined treatment. COMBI therapy was superior to LIRA and MET monotherapy in reducing weight, BMI, and waist circumference. Subjects treated with COMBI lost on average 6.5±2.8 kg compared with a 3.8±3.7 kg loss in the LIRA group and a 1.2±1.4 kg loss in the MET group (P<0.001). The extent of weight loss was stratified: a total of 38% of subjects were high responders who lost ≥5% body weight, 22% of them in the COMBI arm compared with 16 and 0% in the LIRA and MET arm respectively. BMI decreased by 2.4±1.0 in the COMBI arm compared with 1.3±1.3 in LIRA and 0.5±0.5 in the MET arm (P<0.001). Waist circumference also decreased by 5.5±3.8 cm in the COMBI arm compared with 3.2±2.9 cm in LIRA and 1.6±2.9 cm in the MET arm (P=0.029). Subjects treated with liraglutide experienced more nausea than those treated with metformin, but severity of nausea decreased over time and did not correlate with weight loss.
Short-term combined treatment with liraglutide and metformin was associated with significant weight loss and decrease in waist circumference in obese women with PCOS who had previously been poor responders regarding weight reduction on metformin monotherapy.
PMCID: PMC3922503  PMID: 24362411
11.  Retinol-Binding Protein 4 and Insulin Resistance in Polycystic Ovary Syndrome  
Diabetes Care  2008;31(7):1427-1432.
OBJECTIVE—Polycystic ovary syndrome (PCOS) is an insulin-resistant state with insulin resistance being an established therapeutic target; however, measurement of insulin resistance remains challenging. We aimed to 1) determine serum retinol-binding protein 4 (RBP4) levels (purported to reflect insulin resistance) in women with PCOS and control subjects, 2) examine the relationship of RBP4 to conventional markers of insulin resistance, and 3) examine RBP4 changes with interventions modulating insulin resistance in overweight women with PCOS.
RESEARCH DESIGN AND METHODS—At baseline, 38 overweight women (BMI >27 kg/m2) with PCOS and 17 weight-matched control subjects were compared. Women with PCOS were then randomly assigned to 6 months of a higher-dose oral contraceptive pill (OCP) (35 μg ethinyl estradiol/2 mg cyproterone acetate) or metformin (1 g b.i.d.). Outcome measures were insulin resistance (total insulin area under the curve) on an oral glucose tolerance test, RBP4, and metabolic/inflammatory markers.
RESULTS—Overweight women with PCOS were more insulin resistant than control subjects, yet RBP4 levels were not different in women with PCOS versus those in control subjects (35.4 ± 4.3 vs. 28.9 ± 3.1 μg/ml, P = 0.36). RBP4 correlated with cholesterol and triglycerides but not with insulin resistance. Metformin improved insulin resistance by 35%, whereas the OCP worsened insulin resistance by 33%. However, RBP4 increased nonsignificantly in both groups (43.7 ± 6.3 vs. 42.6 ± 5.5 μg/ml, P = 0.92).
CONCLUSIONS—Overweight women with PCOS were more insulin resistant than control subjects, but this finding was not reflected by RBP4 levels. RBP4 correlated with lipid levels but not with insulin resistance markers. RBP4 levels did not change when insulin resistance was reduced by metformin or increased by the OCP. These data suggest that RBP4 is not a useful marker of insulin resistance in PCOS but may reflect other metabolic features of this condition.
PMCID: PMC2453680  PMID: 18390799
12.  Effects of drospirenone pill in Indian women with polycystic ovary syndrome 
To study the effects of treatment with a drospirenone pill (DRSP) (with ethinyl oestradiol, EE) in Indian women with polycystic ovary syndrome (PCOS).
Material and Methods
Fifty-one women with PCOS (Androgen excess society criteria, 2006), with preset inclusion-exclusion criteria, treated with a combination of EE 30 mcg and DRSP 3 mg cyclically in the traditional (21+7) regimen, were evaluated at baseline and after six and twelve cycles of treatment. Parameters studied were - body mass index (BMI), abdominal circumference (AC), Ferriman Galwey (FG) score, presence of acne and acanthosis nigricans, serum testosterone, sex hormone binding globulin (SHBG), fasting glucose and fasting insulin levels. Free Androgen Index (FAI) and Glucose: Insulin ratio (G: I) were calculated.
Significant improvements in clinical and biochemical hyperandrogenic parameters were found at the two points of study. There were no significant changes in BMI, AC, incidence of acanthosis, or metabolic parameters studied.
EE/DRSP improves hyperandrogenic parameters significantly without affecting the insulin resistance adversely in Indian women with PCOS.
PMCID: PMC3939270  PMID: 24591981
Drospirenone pill; polycystic ovary syndrome; androgenic parameters; insulin resistance; Indian women
13.  Medical management of metabolic dysfunction in PCOS 
Steroids  2011;77(4):306-311.
Polycystic ovary syndrome (PCOS) is associated with metabolic derangements including insulin resistance, dyslipidemia, systemic inflammation and endothelial dysfunction. There is a growing need to develop pharmacologic interventions to improve metabolic function in women with PCOS. Medications that have been tested in patients with PCOS include metformin, thiazolidinediones, acarbose, naltrexone, orlistat, vitamin D and statins.
Metformin decreases hepatic gluconeogenesis and free fatty acid oxidation while increasing peripheral glucose uptake. Early studies in PCOS suggested that metformin indirectly reduces insulin level, dyslipidemia and systemic inflammation; however, recent placebo-controlled trials failed to demonstrate significant metabolic benefit. Thiazolidinediones act primarily by increasing peripheral glucose uptake. Most studies in PCOS have demonstrated that thiazolidinediones reduce insulin resistance; however, effects on dyslipidemia were disappointing. Use of thiazolidinediones is associated with weight gain and major complications. Acarbose reduces digestion of polysaccharides. Studies in PCOS yielded inconsistent effects of acarbose on insulin sensitivity and no significant improvement of dyslipidemia. Naltrexone reduces appetite and modulates insulin release; its use in PCOS may reduce hyperinsulinemia. Orlistat decreases absorption of dietary fats; studies in PCOS suggest beneficial effects on insulin sensitivity. Vitamin D may improve insulin sensitivity but mixed results on lipid profile in PCOS have been reported. Statins are competitive inhibitors of the key enzyme regulating the mevalonate pathway; their effects are related to reduced cholesterol production as well as anti-inflammatory and anti-oxidant properties. In women with PCOS, statins reduce hyperandrogenism, improve lipid profile and reduce systemic inflammation while the effects on insulin sensitivity are variable. Use of statins is contraindicated in pregnancy.
PMCID: PMC3409585  PMID: 22182833
Polycystic ovary syndrome; Metabolic dysfunction; Insulin sensitivity; Dyslipidemia; Inflammation
14.  Metabolomics Reveals Reduction of Metabolic Oxidation in Women with Polycystic Ovary Syndrome after Pioglitazone-Flutamide-Metformin Polytherapy 
PLoS ONE  2011;6(12):e29052.
Polycystic ovary syndrome (PCOS) is a variable disorder characterized by a broad spectrum of anomalies, including hyperandrogenemia, insulin resistance, dyslipidemia, body adiposity, low-grade inflammation and increased cardiovascular disease risks. Recently, a new polytherapy consisting of low-dose flutamide, metformin and pioglitazone in combination with an estro-progestagen resulted in the regulation of endocrine clinical markers in young and non-obese PCOS women. However, the metabolic processes involved in this phenotypic amelioration remain unidentified. In this work, we used NMR and MS-based untargeted metabolomics to study serum samples of young non-obese PCOS women prior to and at the end of a 30 months polytherapy receiving low-dose flutamide, metformin and pioglitazone in combination with an estro-progestagen. Our results reveal that the treatment decreased the levels of oxidized LDL particles in serum, as well as downstream metabolic oxidation products of LDL particles such as 9- and 13-HODE, azelaic acid and glutaric acid. In contrast, the radiuses of small dense LDL and large HDL particles were substantially increased after the treatment. Clinical and endocrine-metabolic markers were also monitored, showing that the level of HDL cholesterol was increased after the treatment, whereas the level of androgens and the carotid intima-media thickness were reduced. Significantly, the abundance of azelaic acid and the carotid intima-media thickness resulted in a high degree of correlation. Altogether, our results reveal that this new polytherapy markedly reverts the oxidant status of untreated PCOS women, and potentially improves the pro-atherosclerosis condition in these patients.
PMCID: PMC3241700  PMID: 22194988
15.  Increased serum C-reactive protein levels in normal weight women with polycystic ovary syndrome 
Hippokratia  2011;15(4):323-326.
Background: The clinical spectrum of polycystic ovary syndrome (PCOS) includes components of the metabolic syndrome, such as central obesity, insulin resistance, dyslipidemia, arterial hypertension and, even, disturbances of the clotting mechanism. All these disorders are epidemiologically related to cardiovascular disease, most probably through low-grade intravascular chronic inflammation. The aim of this study was to evaluate the serum concentrations of high sensitivity C-reactive protein (hsCRP), a non-specific marker of low-grade inflammation and a predictive marker for cardiovascular disease, in normal weight women with (PCOS).
Patients and Methods: One hundred and eighty-eight (188) normal weight [body mass index (BMI) < 25 kg/m2] women with PCOS were included in the study. Forty-three (43) normal weight women without PCOS (normal ovulation without clinical or biochemical hyperandrogenemia) served as controls. Serum samples for luteinizing hormone, folliclestimulating hormone, prolactin, total testosterone, Δ4-androstenedione, 17α-hydroxy-progesterone, sex hormone-binding globulin (SHBG), insulin, glucose and hsCRP were collected in early follicular phase (third to sixth day) of a menstrual cycle in the control group or during a spontaneous bleeding episode in the PCOS group.
Results: Normal weight women with PCOS had higher concentrations of serum hsCRP as compared to normal weight women without PCOS (mean ± standard error of the mean 0.55 ± 0.08 versus 0.27 ± 0.08 mg/dL, p = 0.001).
Conclusions: As normal weight women with PCOS are characterized by elevated serum concentrations of hsCRP, they have to be considered as carrying at least one marker of low-grade inflammation.
PMCID: PMC3876847  PMID: 24391413
polycycstic ovary syndrome; high-sensitivity C-reactive protein; inflammation; cardiovascular disease
16.  Metformin therapy in a hyperandrogenic anovulatory mutant murine model with polycystic ovarian syndrome characteristics improves oocyte maturity during superovulation 
Metformin, an oral biguanide traditionally used for the treatment of type 2 diabetes, is widely used for the management of polycystic ovary syndrome (PCOS)-related anovulation. Because of the significant prevalence of insulin resistance and glucose intolerance in PCOS patients, and their putative role in ovulatory dysfunction, the use of metformin was touted as a means to improve ovulatory function and reproductive outcomes in PCOS patients. To date, there has been inconsistent evidence to demonstrate a favorable effect of metformin on oocyte quality and competence in women with PCOS. Given the heterogeneous nature of this disorder, we hypothesized that metformin may be beneficial in mice with aberrant metabolic characteristics similar to a significant number of PCOS patients. The aim of this study was to gain insight into the in vitro and in vivo effects of metformin on oocyte development and ovulatory function.
We utilized metformin treatment in the transgenic ob/ob and db/db mutant murine models which demonstrate metabolic and reproductive characteristics similar to women with PCOS. Results: Metformin did not improve in vitro oocyte maturation nor did it have an appreciable effect on in vitro granulosa cell luteinization (progesterone production) in any genotype studied. Although both mutant strains have evidence of hyperandrogenemia, anovulation, and hyperinsulinemia, only db/db mice treated with metformin had a greater number of mature oocytes and total overall oocytes compared to control. There was no observed impact on body mass, or serum glucose and androgens in any genotype.
Our data provide evidence to suggest that metformin may optimize ovulatory performance in mice with a specific reproductive and metabolic phenotype shared by women with PCOS. The only obvious difference between the mutant murine models is that the db/db mice have elevated leptin levels raising the questions of whether their response to metformin is related to elevated leptin levels and/or if a subset of PCOS women with hyperleptinemia may be responsive to metformin therapy. Further study is needed to better define a subset of women with PCOS that may be responsive to metformin.
PMCID: PMC3121715  PMID: 21605417
polycystic ovarian syndrome; metformin; hyperinsulinemia; oocyte; superovulation
17.  Does adding metformin to clomifene citrate lead to higher pregnancy rates in a subset of women with polycystic ovary syndrome? 
Human Reproduction (Oxford, England)  2008;23(8):1830-1834.
An RCT among newly diagnosed, therapy naive women with polycystic ovary syndrome (PCOS) showed no significant differences in ovulation rate, ongoing pregnancy rate or spontaneous abortion rate in favour of clomifene citrate plus metformin compared with clomifene citrate. We wanted to assess whether there are specific subgroups of women with PCOS in whom clomifene citrate plus metformin leads to higher pregnancy rates.
Subgroup analysis based on clinical and biochemical parameters of 111 women randomized to clomifene citrate plus metformin compared with 114 women randomized to clomifene citrate plus placebo. The data for age, BMI, waist–hip ratio (WHR) and plasma testosterone were available in all women, 2 h glucose in 80% of women and homeostatic model assessment for assessing insulin sensitivity (HOMA) in 50% of women.
Of the women who were allocated to the metformin group, 44 women (40%) reached an ongoing pregnancy. In the placebo group, 52 women (46%) reached an ongoing pregnancy. There was a significantly different chance of an ongoing pregnancy for metformin versus placebo between subgroups based on age and WHR (P = 0.014). There was a positive effect of metformin versus placebo on pregnancy rate in older women (≥28 years) with a high WHR, a negative effect of metformin versus placebo in young women (<28 years) regardless of their WHR and no effect in older, not viscerally obese women. No significant differences in effect of treatment were found for groups based on BMI, 2 h glucose, HOMA or plasma testosterone.
Metformin may be an effective addition to clomifene citrate in infertile women with PCOS, especially in older and viscerally obese patients.
PMCID: PMC2474667  PMID: 18487613
clomifene; metformin; polycystic ovary syndrome; pregnancy; subgroup analysis
18.  The efficacy of metformin and clomiphene citrate combination compared with clomiphene citrate alone for ovulation induction in infertile patients with PCOS 
Low ovulatory and pregnancy rates with clomiphene citrate (CC) in anovulatory polycystic ovarian syndrome (PCOS).
To find out the ovulatory and pregnancy rates in infertile PCOS subjects who receive CC alone and a combination of metformin and CC.
A prospective controlled clinical trial conducted in the outpatient department from August 2003 to August 2005.
Twenty-four infertile PCOS women received CC alone at incremental doses of 50 mg up to 150 mg for three cycles and then at a dose of 150 mg for another three cycles (control group). The study group (16 PCOS) received the same dose of CC along with 1500mg of metformin. Ovulation was monitored by transvaginal sonography up to six cycles or till pregnancy occurred.
This was carried out using software SSPS, version 10. Fisher's exact test was used to calculate the ovulatory rates. Nine subjects of the control group who failed to conceive with CC had opted for CC and metformin and their ovulatory rate was calculated using statistical software, namely SPSS 15.0, Stata 8.0, MedCalc 9.0.1 and Systat 11.0 using Fischer's exact test.
The metformin and clomiphene combination resulted in a significantly higher rate of ovulation (P = 0.0016). The pregnancy rate was 8% with CC and 24% with metformin and CC. The CC failure group also ovulated at a similar rate as that of the study group.
The ovulatory rate and the pregnancy rate with the metformin–CC combination was found to be higher when compared with CC alone. Metformin increased the ovulatory rate in CC failures, also implying increased sensitivity to CC.
PMCID: PMC2700688  PMID: 19562069
Anovulation; clomiphene citrate; clomiphene citrate resistance; metformin; ovulatory rate
19.  Insulin resistance and fertility in polycystic ovary syndrome. 
Journal of Medicine and Life  2008;1(4):415-422.
Polycystic Ovary Syndrome (PCOS) represents a common endocrinopathy, with anovulation and hyperandrogenism as cardinal symptoms. In recent years it has been recognized that insulin resistance is an intrinsec feature of the disorder and plays a central role in pathogenesis. PCOS is associated with important reproductive morbidity as shown by high prevalence of anovulatory infertility, spontaneous abortion, gestational diabetes and pre–eclampsia. The association of insulin resistance with this reproductive pathology has been well documented. Due to major implication of insulin resistance in PCOS pathogenesis, insulin reduction strategies were studied as a possible treatment for infertility in PCOS patients. Weight loss, even modest was proved to be a simple and efficient method to improve reproductive parameters in PCOS patients and should be recommended to all overweight and obese patients with infertility. Metformin was showed to induce ovulation, at least in a subset of patients with PCOS, but there are not unequivocal proves concerning its efficacy for pregnancies and live–birth rate, mainly because few trials studied this aspect. Therefore there are not enough evidences to recommend metformin for infertility treatment in PCOS. Few small studies with newer thiazolidindiones suggest their efficacy for ovulation induction, but further extensive studies are needed to confirm these results. In conclusion, reduction of insulin resistance was proved to ameliorate ovulation rate in PCOS patients, but strong evidences to sustain the utility of insulin–sensitizing drugs as a therapeutic option for infertility are lacking. Future studies are needed to elucidate these aspects and to characterize the particular subtype of patients with higher probability to respond to this treatment.
PMCID: PMC3018970  PMID: 20108521
20.  Effect of Treatment with Metformin on Omentin-1, Ghrelin and other Biochemical, Clinical Features in PCOS Patients 
Oman Medical Journal  2010;25(4):289-293.
Polycystic ovary syndrome is associated with insulin resistance and obesity. Previous studies suggest that metformin by reducing hyperinsulinemia is clinically useful in the treatment of polycystic ovary syndrome. This study’s Objective is to observe the role of metformin in omentin1, ghrelin, and other biochemical, clinical features within three months in hyperinsulinemic women with polycystic ovary syndrome. Another aim is to assess the decrease in hyperinsulinemia and body weight by metformin in the population.
This study was carried out at the Kamal AL-Samarai Hospital between June 2007 and March 2008. 60 women fulfilling the clinical and biochemical criteria for polycystic ovary syndrome and hyperinsulinemia were enrolled. Metformin was started at an oral dose of 850 mg/day for 3 months. Besides Body Mass Index (BMI), Waist Hip Ratio (WHR), serum omentin1, ghrelin, fasting insulin, fasting blood sugar and lipid profile levels were performed. After three months, all these parameters were assessed. Omentin1, ghrelin and insulin were measured by enzyme-linked immunosorbent assay, fasting blood glucose and lipid profile were measured by colorimetric methods.
Mean Body Mass Index and Waist Hip Ratio had significantly decreased in the 60 polycystic ovary syndrome patients after three months of Metformin therapy. Serum levels of omentin1, ghrelin and HDL-cholesterol were increased while the total cholesterol/HDL cholesterol ratio was decreased significantly. Serum concentrations of insulin, Homeostatic Model Assessment (HOMA) and HOMA ß-cell % were also decreased significantly, the present study showed a significant increase in omentin1: insulin ratio, omentin1: HOMA ratio and omentin1: HOMA ß-cell% ratio.
There was a significant an increase in omentin1: insulin ratio, omentin1: HOMA ratio and omentin1: HOMA ß-cell% ratio. These results in the present study are shown the first time, these factors may be useful in following improvements in insulin sensitivity in subjects with polycystic ovary syndrome or obesity treated with insulin sensitizers. Further studies are needed to certify these factors in other populations with these treatment or with other insulin sensitizers or when treated with diet and exercise.
PMCID: PMC3191665  PMID: 22043360
21.  Treatment of premenstrual dysphoric disorder (PMDD) with a novel formulation of drospirenone and ethinyl estradiol 
Premenstrual dysphoric disorder (PMDD) is a severe form of premenstrual syndrome (PMS). Pharmacologic options studied for treating severe PMS and PMDD may include selective serotonin reuptake inhibitors, anxiolytic agents, gonadotropin-releasing hormone agonists and the diuretic spironolactone. However, the use of combined oral contraceptives (COC) may be a therapeutic option in treating PMS and PMDD. The combination of drospirenone with ethinylestradiol (EE/drospirenone) was approved for marketing as an oral contraceptive in Europe and the United States. The preparation is characterized by a high contraceptive efficacy in combination with excellent cycle control, good tolerability, and a favourable impact on lipid and glucose metabolism. Recently, some placebo-controlled, randomized studies have tested clinical efficacy and tolerability of this COC in the treatment of PMDD. The aim of the present review was to elucidate the possible benefits or disadvantages of PMDD treatment with this novel formulation of EE/drospirenone. The results of trials evaluating the use of EE/drospirenone combination in the treatment of PMDD are encouraging but further studies are needed. However, the reported clinical efficacy and the relative good tolerability of EE/drospirenone may contribute to widen the therapeutic spectrum of PMDD.
PMCID: PMC2374943  PMID: 18472980
Premenstrual dysphoric disord©er; oral contraceptives; drospirenone; ethinylestradiol; efficacy; tolerability
22.  Anteroposterior diameter of the infrarenal abdominal aorta is higher in women with polycystic ovary syndrome 
Women affected by polycystic ovary syndrome (PCOS) are known to be at higher risk of cardiovascular disease. The aim of this study was to identify the artery that first is affected by early pre-atherosclerotic changes in PCOS.
Twenty-nine women with PCOS aged 17 to 27 years and 26 healthy nonhyperandrogenic volunteers with regular menses (control women) aged 16 to 28 years were enrolled. All PCOS patients were overweight or obese (body mass index [BMI] ≥ 25). Diagnosis of PCOS was performed in line with the 2003 Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Accordingly, PCOS was defined when at least two of the following three features were present after exclusion of other etiologies: 1) oligomenorrhea and or anovulation; 2) hyperandrogenism and/or hyperandrogenemia; and 3) polycystic ovaries visible at ultrasound. Androgen excess or related disorders were excluded. The intima-media thickness (IMT) of common carotid arteries and common femoral arteries and the anteroposterior diameter of the infrarenal abdominal aorta were measured by ultrasound. Lutenizing hormone (LH), follicle-stimulating hormone (FSH), estradiol, total testosterone, androstenedione, and sex hormone-binding globulin (SHBG) serum levels were measured between the 3rd and the 6th day of spontaneous or progestin-induced menstrual cycle. Our study was performed in the absence of any medical treatment.
Women with PCOS showed a higher LH to FSH ratio (p < 0.01), increased fasting insulin (p < 0.001), total testosterone (p < 0.001), and androstenedione (p < 0.001) levels, and lower SHBG concentrations (p < 0.001) compared to control women. BMI and waist-to-hip ratio were also higher in women with PCOS (p < 0.000 and p < 0.001, respectively). Women with PCOS also showed increased total cholesterol (p < 0.001), triglyceride (p < 0.001), and apolipoprotein B (p < 0.001) levels. Vascular data showed women with PCOS had a higher anteroposterior diameter than control women (p < 0.005). However, when analysis of covariance was performed and BMI was entered into the model as a covariate, anteroposterior diameter did not maintain a significant association with PCOS.
This study shows that anteroposterior diameter of the infrarenal abdominal aorta, but not IMT of common carotid arteries or common femoral arteries, is higher in women with PCOS than in women without this disease. This represents the earliest atherosclerotic change in women with PCOS. However, this alteration seems to be due to body weight secondary to PCOS and not due to PCOS per se.
PMCID: PMC2704897  PMID: 19590590
polycystic ovary syndrome; antero-posterior diameter; infrarenal abdominal aorta; intimia-media thickness
23.  Can Sex-hormone Binding Globulin Considered as a Predictor of Response to Pharmacological Treatment in Women with Polycystic Ovary Syndrome? 
This study aims to evaluate the sex hormone binding globulin (SHBG) level as a predictor of response to pharmacological treatment in women with polycystic ovary syndrome (PCOS).
This study was conducted in 2009-2012 in Isfahan, Iran. Anovulatory women with a diagnosis of PCOSwere studied. Metformin was started at 500 mg three times a day. If no ovulation occurred, Clomiphene citrate was added.
The study comprised273 infertile women with PCOS completed the study, 75 (28%) of them became pregnant 6 months after treatment (7.36% with metformin and 20.14% with metformin and clomiphene citrate). Patients who responded to metformin treatment had significantly lower mean SHBG levels compared to those who did not (0.88+0.32vs. 0.2642+0.44 nmol/L, respectively, P<0.0001). The area under the ROC curve (AUC) for prediction the response to treatment was 0.85. The baseline level of 27was the most appropriate cut of point HSBG for the prediction of conception. HSBG had a sensitivity of 88%, and specificity of 73.6%. It had a false positive level of 26.4% and false negative level of 12%. Its positive predictive value was 56.4% and its negative predictive value was 94%. The chance of conception increased for reducing a unit of fpg (OR = 0.69; 95% CI = 0.54-0.86; P = .002), as well as reducing of every unit of HSBG (OR = 0.47; 95% CI = 0.39-0.56; P <0.001), and for reducing each unit of insulin in (OR = 0.082; 95% CI = 1.021-0.33; P <0.001).
HSBG test is suggested as an appropriate test for predicting pregnancy achievement of PCOs women after pharmacological treatment
PMCID: PMC3843304  PMID: 24319557
Binding globulin; metformin; polycystic ovary syndrome; sex-hormone
24.  Serum C-Reactive Protein Levels in Normal-Weight Polycystic Ovary Syndrome 
Serum levels of highly sensitive C-reactive protein (hsCRP), a vascular inflammatory marker, may predict the development of cardiovascular disease (CVD) and type 2 diabetes. Women with polycystic ovary syndrome (PCOS) are at greater risk for type 2 diabetes and CVD. The aim of this study was to compare hsCRP levels between normal weight women with PCOS and controls with a normal menstrual cycle and to determine the factors associated with serum hsCRP levels.
Thirty-nine lean PCOS patients and 24 healthy, regular cycling women were enrolled in this study. We performed anthropometric measurements, fat computed tomography (CT), and blood sampling to determine blood chemistry and levels of hsCRP, gonadotropins, testosterone, and sex-hormone binding globulin. We also conducted 75-g oral glucose-tolerance test and euglycemic hyperinsulinemic clamp to assess insulin sensitivity.
Serum hsCRP concentrations were higher in women with PCOS than in women with regular mensturation. However, this difference was no longer significant after adjusting for body mass index (BMI). hsCRP levels were correlated with waist circumference (r=0.46, p<0.01), BMI (r=0.46, p<0.01), visceral fat area (r=0.45, p<0.01), and systolic (r=0.42, p<0.05) and diastolic blood pressure (r=0.39, p<0.05). hsCRP also tended to be negatively associated with insulin-mediated glucose uptake (IMGU) (r=-0.31, p=0.07). A multiple regression analysis revealed that BMI (β=0.29, p<0.05), systolic blood pressure (β=0.39, p<0.01), and IMGU (β=-0.31, p<0.05) predicted serum hsCRP levels in women with PCOS.
PCOS by itself does not seem to be associated with increased hsCRP levels, whereas known CVD risk factors affect serum hsCRP levels in PCOS.
PMCID: PMC2784979  PMID: 19949734
Cardiovascular disease; C-reactive protein; Polycystic ovary syndrome
25.  Altering Hirsutism Through Ovulation Induction in Women With Polycystic Ovary Syndrome 
Obstetrics and Gynecology  2012;119(6):1151-1156.
Many women with polycystic ovary syndrome (PCOS) experience infertility and hirsutism and often seek treatment for both concurrently. We investigated whether women who ovulate in response to treatment with clomiphene citrate), metformin, or both would have greater improvement in hirsutism compared to those who did not ovulate.
This is a secondary analysis evaluating the change in Ferriman-Gallwey score for the hirsute women (n = 505, 80.7%) from the Pregnancy in Polycystic Ovary Syndrome 1 study. This was a prospective, randomized, doubled-blind trial of 626 women with PCOS and infertility recruited from 12 university sites. They were treated with clomiphene citrate, metformin, or both (combination) for up to six cycles, and hirsutism evaluators were blinded to group assignment.
There was a significant decrease in the Ferriman-Gallwey score between baseline and completion of the study in each of the three individual groups (clomiphene citrate, p=0.024; metformin, p=0.005; combination, p<0.001). There was no significant difference in the degree to which the hirsutism score changed when comparing the three groups (p=0.44). The change in hirsutism was not associated with the duration of treatment or with the presence or absence of ovulation.
In infertile hirsute women with PCOS, treatment with clomiphene citrate, metformin, or both for up to 6 cycles does not alter hirsutism.
Clinical Trial Registration,, NCT00068861.
PMCID: PMC3360417  PMID: 22617579

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