|Year : 2014 | Volume
| Issue : 2 | Page : 112-117
Comparison of efficacy and safety of metformin, oral contraceptive combination of ethinyl estradiol and drospirenone alone or in combination in polycystic ovarian syndrome
Jyoti A. Bobde, Deepak Bhosle, Rajesh Kadam, Satish Shelke
Department of Pharmacology, MGM Medical College, Aurangabad, Maharashtra, India
|Date of Submission||17-Feb-2014|
|Date of Decision||17-Apr-2014|
|Date of Acceptance||13-Apr-2014|
|Date of Web Publication||12-Jun-2014|
Department of Pharmacology, MGM Medical College, Aurangabad, Maharashtra
Source of Support: None, Conflict of Interest: None
Introduction: Polycystic ovarian syndrome (PCOS) is a common endocrine disorder, which can cause various reproductive complications and is associated with metabolic syndrome. In India, strong comparative evidence of oral contraceptive pills (OCP), metformin or their combination in treatment of polycystic ovarian disease is lacking. Objectives: The objective of this study is to compare the efficacy and safety of metformin alone, OCP containing drospirenone or a combination of OCP and metformin in patients with PCOS. Materials and Methods: This was an open-label, randomized, parallel group, and comparative three-arm prospective study, in 60 patients. Patients either received OCPs containing etinyl estradiol plus drospirenone, metformin or combination of OCPs plus metformin for 6 months. Luteinizing hormone: Follicle stimulating hormone (LH:FSH) ratio, serum insulin level, ovarian morphology, body mass index (BMI), acceptance of treatment, regularization of the menstrual cycle and improvement in acne and hirsuitism were evaluated. Results: In patients receiving metformin either as monotherapy or in combination showed significant improvement in BMI. All the study medicines were effective in significantly decreasing ovarian volume, LH/FSH ratio and serum insulin level. Improvement in acne was better in patients receiving OCPs either as monotherapy or in combination with metformin. Improvement in hirsuitism and regularization of the menstrual cycle was highest in patients receiving combination treatment. Acceptance of treatment was maximum in patients receiving monotherapy of OCPs. The total incidence of adverse events was 16.7% (15%, 15% and 20% in OCP, metformin, and combination group, respectively). Conclusion: OCPs containing ethinylestradiol plus drospirenone, metformin, and combination of both are effective and well tolerated in the management of PCOS. Metformin either as monotherapy or combination can be preferred in cases with high BMI. Combination of metformin plus OCP regularizes menstrual cycle better than monotherapy of either drug.
Keywords: Efficacy, metformin, oral contraceptive pills, polycystic ovarian syndrome, safety
|How to cite this article:|
Bobde JA, Bhosle D, Kadam R, Shelke S. Comparison of efficacy and safety of metformin, oral contraceptive combination of ethinyl estradiol and drospirenone alone or in combination in polycystic ovarian syndrome. J Obes Metab Res 2014;1:112-7
|How to cite this URL:|
Bobde JA, Bhosle D, Kadam R, Shelke S. Comparison of efficacy and safety of metformin, oral contraceptive combination of ethinyl estradiol and drospirenone alone or in combination in polycystic ovarian syndrome. J Obes Metab Res [serial online] 2014 [cited 2018 Dec 17];1:112-7. Available from: http://www.jomrjournal.org/text.asp?2014/1/2/112/134426
| Introduction|| |
Polycystic ovarian syndrome (PCOS) is a common endocrine disorder, which can cause menstrual disturbances, ovulation disorder, miscarriage, pregnancy-related complications and metabolic syndrome.  The exact prevalence of PCOS in India is unknown. As per a study from South India, the prevalence of PCOS in Indian adolescents is 9.13%.  Women with PCOS are at risk of metabolic syndrome and associated comorbidities.  Insulin resistance is known to play a significant role in the pathogenesis of PCOS.  The initial presentation of PCOS is often during the adolescent years; hence, its management deserves special consideration. Symptomatic therapy based on the main complaint remains the treatment of choice for PCOS. Individualized therapy should include steroid hormones, antiandrogens, and insulin sensitizing agent.  Patients on antiandrogen may suffer from irregular uterine bleeding. Antiandrogens may be beneficial only when it is combined with estradiol containing combination pills.  The combination pills containing estradiol and progestin are used in the long-term treatment of PCOS for giving endometrial protection, regularizing menses and improving hirsutism and/or acne by reducing the production of ovarian androgens.  Close to 50% of women with PCOS are overweight and one-third become diabetic over the period of time. PCOS is associated with an increase in testosterone, luteinizing hormone (LH), and insulin levels. The main goals of treatment for PCOS in adolescent are to regulate menstrual functions, reduce androgen and insulin levels, and improve dermatologic symptoms. Often, as insulin levels are reduced, androgen levels are lowered and menses may become more regulated.  No single treatment is universally effective; most studies have shown conflicting results. Oral contraceptive pills (OCPs) are considered to be among the primary treatment options for PCOS, particularly for patients who want to avoid pregnancy. Estrogen increase serum hormone binding globulin production, leading to decrease in circulating free androgens. Progestin protects the endometrium against unopposed estrogen stimulation induced hyperplasia. The androgenicity of the progestin varies depending on the dosage used and on androgen measurement indices. Some progestins, such as drospirenone and cyproterone acetate, have proven antiandrogenic effects and hence can have an additional benefit. Combined OCP results in suppression of LH and follicle stimulating hormone (FSH) with less ovarian stimulation and androgen production. 
Metformin can improve insulin action, and reduce circulating insulin level. A reduction in insulin level can result in an increase in serum hormone-binding globulin and thus reduction in androgen levels. Metformin has also been shown to increase ovulation in women with PCOS. Abnormalities of the insulin receptor are more common in Indian women with PCOS compared to white women with PCOS.  Metformin has an advantage over OCPs in terms of reducing insulin resistance. Newer OCPs containing drospirenone having anti-androgenic effect may be beneficial for patients with PCOS. In India, evidence comparing OCPs, metformin or their combination in the treatment of poly cystic ovarian disease is limited.
The objective of this study is to compare the efficacy and safety of metformin alone, OCP containing drospirenone or a combination of OCP and Metformin in patients with polycystic ovarian disease in adult women.
| Materials and methods|| |
In an open label, randomized, parallel group, comparative three arm prospective study, a total of 60 patients between 15 and 25 years diagnosed with PCOS according to Rotterdem criteria, and willing to participate, after written informed consent, were enrolled. All the patients were unmarried girls with history of hirsuitism/acne or both. Patients with thyroid disease, diabetes, adrenal disorders, hyperprolactinemia, having a history of migraine, hypertension, thromboembolic events, and known hypersensitivity to study drugs were excluded from the study. Patients with history of smoking, alcoholism, those with clinically significant cardio vascular disease, renal disease, or hepatic disease were also not included in the study.
The enrolled patients were randomly assigned to one of the following three groups of 20 each by a lottery method. The study medicines were given for 6 months. The drugs and dosage of medicine in three groups are:
- Group I received OCPs containing etinyl estradiol 20 μg + drospirenone 3 mg -1 tablet daily (24 days active pill and 4 days inactive pills)
- Group II received metformin 500 mg tds
- Group III received OCPs containing ethinyl estradiol 20 μg + drospirenone 3 mg -1 tablet daily (24 days active pills and 4 days inactive pills) plus metformin 500 mg tds
Vital signs were recorded along with physical examinations and systemic examinations. Detailed past medical history and history of concomitant medicines were taken before starting treatment.
All the patients were screened on the 2 nd day of the menstrual cycle for hormonal assay and transabdominal ultrasound sonography pelvis. Fasting blood sample was collected and hormonal assay was done on Immulite 1000 (Siemens Healthcare Global). Convex curvilinear transducer of 4 mHz frequency was used for ultrasound examination. Sonographic features of PCOS include the presence of 12 or more follicles in each ovary with 2-9 mm diameter and/or increased ovarian volume (>10 mL). This is regardless of follicle distribution or ovarian stromal echogenicity. One ovary fulfilling this definition is sufficient to define PCOS. Ovarian volume more than 10 mL was considered as PCOS. , Patients were evaluated at baseline and at 1 st , 3 rd , and 6 th month. Compliance was checked and adverse event were reported during followup visits.
Hormonal assay for estimation of LH:FSH ratio and serum insulin level, pelvic ultrasound for ovarian morphology and ovarian volume and body mass index (BMI) were the objective evaluation parameters. Acceptance of treatment was assessed by asking a question "Whether you would like to continue with the treatment after the study?" Regularization of the menstrual cycle was assessed by asking a question "Whether your menstrual cycle has been regularized?" Similarly, improvement in acne and hirsuitism were evaluated by asking subjective questions.
Paired t-test was used for assessing the difference between before-and-after values within each group. ANOVA test was used to measure the differences among the groups. Chi-square test was used to estimate the difference between three groups for acne, hirsuitism, regularization of the menstrual cycle and acceptance of treatment. P < 0.05 was considered as statistically significant.
| Results|| |
This study was conducted in collaboration with the Department of Obstetrics and Gynecology at MGM Medical College, Aurangabad. The study was conducted in compliance with the protocol and as per the ICH/GCP Guidelines. The study was approved by the institutional Ethics Committee.
[Table 1] shows the distribution of patients in different age groups.
Acne was present in 20%, 35%, and 25% patients in Groups I, II, and III, respectively [Table 2] while hirsuitism was present in 40%, 30%, and 45% patients, respectively.
In patients from Group II to III, the reduction in BMI was significant (P < 0.05) while there was no significant difference in the BMI in Group I (P > 0.05) [Table 3]. There was a significant difference in three groups in reducing BMI.
Significant decrease in ovarian volume was seen with treatment in all the groups (P < 0.05) [Table 3]. After treatment, there was no significant difference between three groups in terms of the ovarian volume after treatment.
Treatment in all three study groups resulted in a significant reduction in LH/FSH ratio (P < 0.05) [Table 3]. There was no statistically significant difference between the three groups in reducing LH/FSH ratio.
All the groups were significantly effective in reducing the serum insulin level (P < 0.05) [Table 3]. There was no significant difference between the three groups in reducing serum insulin level.
There was a significant difference in the three groups in improvement of acne and hirsuitism (Chi-square test P < 0.05). Improvement in acne was seen in 100% patients in Group I and III [Figure 1]. Highly significant difference in three groups was seen in regularizing menstrual cycles (Chi-square test P = 0.0001). Improvement in hirsuitism and regularization of the menstrual cycle was highest in patients receiving combination treatment [Figure 1].
Acceptance of treatment was maximum in Group I, while least in Group III [Figure 2].
Study medicines were generally well tolerated by the patients. The total incidence of adverse events in the study was 16.7%. The incidence of adverse events in Groups I, II, and III was 15%, 15%, and 20%, respectively. No serious adverse drug events were reported in the study. In the metformin group, nausea and metallic taste were reported by two and one patient, respectively. In the combination group, three patients reported nausea while vomiting occurred in one patient. Among patients receiving only OCP mild nausea and intermenstural spotting were reported by one and two patients, respectively.
| Discussion|| |
Conventional treatment for PCOS is targeted to suppress ovarian testosterone production using the combined OCP. In some women, the OCP is not appropriate treatment because of side-effects like increased risk of thrombosis, which is higher in obese women. In some patients, it is associated with weight gain which might worsen the PCOS symptoms in the long run. Hence, alternative options are used for getting good effect. The focus of this new approach is the insulin axis. In insulin resistance, high amounts of insulin is required to maintain normal glucose levels. Hyperinsulinemia causes excess of ovarian stimulation to produce androgens. Reducing insulin by lifestyle modifications or drugs results in lowering of androgen and improved symptoms of PCOS.  Insulin-sensitizing agents have positive effects on insulin resistance, menstrual irregularities, anovulation, hirsutism, and obesity-metformin is one such useful agent.  This study analyzed the efficacy and safety of OCPs or metformin alone or in combination in the management of PCOS.
The pharmacological profile of drospirenone is more closely related to that of progesterone, especially with regard to antimineralocorticoid and antiandrogenic activities. The other concern regarding long-term use of OCP containing drospirenone is venous thromoembolism, which was exaggerated in obese women. 
One of the causes of PCOS is considered as insulin resistance. Hence, insulin sensitizers are indicated in PCOS patients who also have positive effects on insulin resistance, menstrual irregularities, anovulation, hirsutism, and obesity. Of all the drugs used to treat manifestations of PCOS, metformin has the most data supporting its effectiveness. 
In this study, all enrolled patients were suffering from oligomenorrhea. Decrease in mean BMI was seen in each group, which was statistically significant in metformin and combination group indicating no significant weight reduction with OCPs; however, metformin alone or its combination with OCPs resulted in a significant reduction in BMI.
Oelkers et al. have reported that due to anti-mineralocorticoid effect of drospirenone, there is a slight decrease in body weight.  Anti-mineralocorticoid action might be responsible for no significant decrease in body weight with OCP. According to studies conducted by Cinar et al., Ibαρez and de Zegher weight loss with metformin was more compared to the OCP containing drospirenone. , More weight loss with metformin could be due to its anorexic property and counteracting adipose tissue expansion through direct inhibition of adipogenesis.  The difference in the LH:FSH ratio in three groups was not statistically significant. The significant decrease in LH by metformin compared to OCP with drospirenone has been shown by Pirwany et al.  Ovarian volume was reduced in all groups; however, no significant difference was seen in three groups showing no group was better over the other in reducing the ovarian volume. With a reduction in LH level, there is also a reduction in ovarian volume. This finding of our study is supported by Pache et al. study. Using two-dimensional ultrasound, Pache et al. have reported a statistically significant relationship between ovarian volume with serum LH and testosterone concentrations. 
All drugs were effective in reducing serum insulin level, but there was no significant difference in reduction. Significant reduction in serum insulin was seen with metformin in a study conducted by Kowalska et al. 
Regularization of menstrual cycles is usually the concern for most patients. In our study, metformin was less effective than the OCPs in improving menstrual pattern, which is supported with the study by Costello et al.  LH plasma levels are reduced by decreased LH pulse amplitude, and it takes almost 4-6 months for normalizing the LH plasma levels in patients on metformin monotherapy. Possibly due to this reason the regularization of cycles was delayed in metformin recipients compared to the OCP. OCP users had monthly withdrawal bleeding due to the hormonal free interval in the monthly cycle, which was responsible for regularizing cycles in OCP and the combination group. OCPs were better in controlling acne as is evidenced by maximum response in reducing acne seen with OCP and combination group in our study. It is supported by the study of Palep Singh et al., stating that drospirenone-containing OCPs decreases the severity of acne in women with PCOS.  Metformin only reduces the androgens, but OCPs with drospirenone decreases androgens and also have androgen receptor blocking activity.
The maximum improvement in hirsuitism was seen in the combination group followed by OCPs and least in the metformin group. The results are in line with Cosma et al.  who showed that the improvement in hirsuitism with metformin was inferior compared to spironolactone. We observed that OCP is better than metformin in improving hirsuitism. Progestin content of OCP used in the study is also a derivative of spironolactone. This could be the probable cause for the results in our study. It has been reported that the addition of metformin slightly modifies the treatment effect of OCPs resulting in more significant reduction in the free-androgen index and may be responsible for better response with the combination group.  The results of our study show that the treatment for PCOS is no longer only symptomatic, but should aim to reverse the basic pathological mechanism like insulin resistance.
Oral contraceptive pills and metformin both are commonly used medicines in clinical practice and the safety of these drugs is well-established. In the current study, only mild adverse drug reaction were reported, which resolved by symptomatic treatment.
The patients in the current study reported better acceptance with OCPs followed by metformin and least with the combination therapy, which could be because of less side-effects of nausea and vomiting. The other reason may be related to compliance with medicine use. OCPs were to be taken only once at bed time compared to metformin to be taken 3 times a day and same for the combination group.
Limitations of the current study include small sample size, and open label design. Large randomized studies are needed to confirm the results of this study.
| Conclusion|| |
Oral contraceptive pills containing ethinylestradiol plus drospirenone, metformin and combination of both are effective and well-tolerated in the management of PCOS. Metformin has an advantage of beneficial effects on BMI. Combination of metformin plus OCP scores over metformin, or OCP monotherapy in regularization of the menstrual cycle, improvement of acne, and hirsuitism.
| Acknowledgment|| |
Authors of this manuscript wish to thank Dr. Anant D. Patil for his support in writing the manuscript.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]