Introduction
Polycystic ovary syndrome (PCOS) is an endocrine disorder affecting approximately 10% of women in reproductive age. It is associated with a variety of hormonal abnormalities such as menstrual irregularity, insulin resistance, clinical hyperandrogenism or hyperandrogenemia, and infertility. The reduction in testosterone level is one of the most common outcomes reported in clinical trials and is frequently used by clinicians to assess the progress of a patient’s condition.
Current guidelines recommend lifestyle modifications and weight reduction for all patients with PCOS, along with combined oral contraceptives (COCs), metformin, or spironolactone, individualized based on the patients’ presentation. The use of statins has been recently introduced as a therapeutic option for PCOS, either alone or in combination with metformin or COCs. This article aims to evaluate the effectiveness of different statins alone or in combination with metformin in treating patients with PCOS, addressing the controversies surrounding the role of statins and their importance for patients with PCOS.
Methods of Analysis
A systematic review was conducted using Medline, Embase, and clinicaltrials.gov for studies using COCs, statins, spironolactone, and metformin for treatment of patients with PCOS. The patients, intervention, comparator, outcome, and study design (PICOS) strategy was used to identify relevant terms, and search terms included polycystic ovary syndrome and antiandrogen. The search was limited to peer-reviewed randomized clinical trials (RCTs) that were conducted in humans and published in English.
Data were extracted from the included studies by two independent investigators, and verified by a third investigator. For each study, the reduction in total testosterone reported as mean difference (MD) and standard deviation (SD) were extracted from studies as our primary outcome. A frequentist network meta-analysis using random-effects models was used to assess the efficacy in reducing testosterone levels and were expressed as odds ratio (OR) and 95% credible interval (95%Crl). All statistical analyses and inconsistency tests were performed using netmeta Version 1.0 on R statistical package. The study was conducted according to the preferred reporting items for systematic reviews and meta-analyses for network meta-analyses (PRISMA-NMA).
Results of the Study
A total of 281 articles were identified in the systematic search, and among these 9 articles were included in the network meta-analysis. The interventions in the included studies were COCs, atorvastatin, simvastatin, spironolactone, simvastatin plus metformin (SmivMet), metformin plus spironolactone (MetSpiro), metformin alone, and placebo. There was a direct comparison between atorvastatin and placebo and between simvastatin and metformin; however, no trials made a direct comparison between statins and other therapies. Therefore, a network meta-analysis deemed necessary to provide an indirect comparison between the interventions.
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When compared to metformin, the pairwise comparison showed no significant difference in reducing the testosterone level for all management strategies. In the network meta-analysis, atorvastatin showed greater reduction in testosterone level compared to COC (MD −2.78, 95%CrI −3.60, −1.97), spironolactone plus metformin (MD −2.83, 95%CrI −3.80, −1.87), simvastatin (MD −2.88, 95%CrI −3.85, −1.92), spironolactone (MD −2.90, 95%CI −3.77, −2.02), simvastatin plus metformin (MD −2.93, 95%CrI −3.79, −2.06), metformin (MD −2.97, 95%CrI −3.69, −2.25), lifestyle modification (MD −3.02, 95%CrI −3.87, −2.18), and placebo (MD −3.04, 95%CrI −3.56, −2.53).
Comparative Efficacy of Interventions in PCOS
Metformin was the only management strategy that was evaluated directly to most of the other strategies. The study evaluated the effect of atorvastatin in reducing testosterone levels in women with PCOS utilizing the network-meta analysis technique to provide a direct and indirect comparison of all interventions used to treat PCOS, with the goal of providing a comprehensive picture of statins alone or as add-on therapy with metformin or COC for clinicians and patients.
Discussion on Atorvastatin and PCOS
The study found that atorvastatin provided a greater reduction in testosterone levels in patients with PCOS when compared to COC, spironolactone plus metformin, simvastatin, spironolactone, simvastatin plus metformin, metformin, lifestyle modification, and placebo, respectively.
The pros and cons of atorvastatin use in improving PCOS symptoms have been addressed in the literature . It has been shown that using atorvastatin for a duration of more than 12 weeks had substantially improved PCOS symptoms, yet, it impairs insulin sensitivity. However, to our knowledge, this is the first study to compare between atorvastatin and all interventions in terms of reducing the testosterone level in patients with PCOS. Initially, we have combined atorvastatin and simvastatin as one group (statins); however, this led to a significant inconsistency (p-value < 0.05). Hence, we have separated the atorvastatin and the simvastatin into two groups.
COC is the first line of treatment in patients with PCOS as it provides a great remission for PCOS symptoms; however, it prevents patients from conceiving if they want to be. Metformin alone, as the first line of treatment, allows patients to conceive, but it is inferior in terms of resolving PCOS symptoms. From the current study, atorvastatin was found to be better in reducing testosterone levels, which would resolve PCOS symptoms without interfering with the ability to conceive.
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Limitations of the Study
The main limitations of our network meta-analysis are the significant heterogeneity among the included studies. The nine studies that were included in the NMA used different diagnostic criteria for PCOS, leading to different types of participants were included. Also, different types and doses of statins were used, which could have affected the outcome of the study. The baseline characteristics for the participants in the trials differed in terms of age, BMI, and ethnicity, which may have affected the results. Moreover, the design for the studies, drug dosage, and follow-up duration, thus it may have affected the results. Finally, in the current study, we only evaluated the interventions based on the change in the testosterone level, which might limit the utilization of the results to patients with a high level of testosterone only.
Additional Insights on PCOS and Metformin
PCOS, a combination of oligomenorrhea or anovulation with hyperandrogenism, affects approximately 5 to 7 percent of women of reproductive age. This neuroendocrine abnormality may be caused by elevated luteinizing hormone (LH) levels and more frequent pulses of LH secretion. Women with hyperandrogenism also have increased insulin resistance, which manifests as increased body mass index (BMI), increased waist-to-hip ratio or, in severe cases, acanthosis nigricans. The combination of severe insulin resistance and LH stimulation results in increased ovarian secretion of testosterone, leading to the virilizing features of PCOS. The syndrome should be suspected in women with hirsutism, irregular menstruation, or infertility. Traditional treatment involves the use of clomiphene therapy and weight loss for sub-fertility, and combination oral contraceptives plus spironolactone for hirsutism.
Metformin is effective in achieving weight loss in women with PCOS. It potentiates the low-calorie diets typically used to achieve the BMI of 20 to 25 kg per m2 that is necessary for the return of ovulation. In one study of 150 obese women, a 10 percent reduction in BMI was achieved with metformin therapy. In another study, metformin plus a low-calorie diet was superior to the low-calorie diet alone for weight loss in women with PCOS. The weight loss action of metformin appears to be caused by the reduction in insulin resistance as well as by appetite suppression.
The effects of metformin on menstrual function and infertility may be caused by decreased insulin resistance and lowered testosterone levels. In a long-term study of 23 women with PCOS, one half of those treated with metformin resumed regular menstruation. The effect appears to increase with duration of treatment. Studies of women who were treated for at least six months report that more than 90 percent of women resumed regular menstruation. Four to six months of therapy are thought to be necessary for ovulation to commence.
In studies, about 5 percent of patients discontinued metformin therapy because of side effects, but more than one half of patients reported diarrhea, and one fourth experienced other gastrointestinal upsets. A rare but potentially serious side effect is lactic acidosis in patients with renal insufficiency. Metformin in dosages of 1,500 to 2,550 mg per day addresses the major aspects of PCOS management and is expected to become more widely used to treat this syndrome. Because of the gastrointestinal side effects of metformin, the usual starting dosage is 500 mg taken with the largest meal of the day. If tolerated, the dosage is gradually increased to 500 mg with each meal.
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