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BACKGROUND: Polycystic ovarian syndrome (PCOS) is a common disease. There is limited abstract
evidence to support various treatment choices. This leads to variable treatment practices.
OBJECTIVES: To conduct a systematic review and meta-analysis of randomized controlled
trials (RCTs) to evaluate the use of metformin versus oral contraceptive pills (OCPs) for the
treatment of PCOS in adolescents aged 11 to 19 years.
DATA SOURCES: We performed literature searches through Ovid Medline, Ovid Embase,
Cochrane Central Register of Controlled Trials, and gray literature resources, up to January
29, 2015.
STUDY SELECTION AND DATA EXTRACTION: Two reviewers screened titles and abstracts of identified
citations, assessed full text eligibility, and extracted information from eligible trials.
RESULTS: Four RCTs met the inclusion and exclusion criteria. The reviewed evidence came
from 170 patients. Overall, OCP treatment resulted in modest improvement in menstrual
cycle frequency (weighted mean difference [WMD] = 0.27, P < .01, 95% confidence interval
[CI] −0.33 to −0.21) and mild reduction of acne scores (WMD = 0.3, P = .02, 95% CI 0.05 to
0.55). While metformin resulted in greater BMI reduction (WMD = −4.02, P < .01, 95% CI
−5.23 to −2.81) it was associated with decreased dysglycemia prevalence (risk ratio: 0.41,
P = .02, 95% CI 0.19 to 0.86) and improved total cholesterol and low-density lipoprotein
levels. Metformin and OCPs were similar in terms of impact on hirsutism.
CONCLUSIONS AND LIMITATIONS: Current evidence is derived from very low to low quality evidence.
Therefore, treatment choice should be guided by patient values and preferences while
balancing potential side effects. Future high quality RCTs are needed to address several
questions for the treatment of adolescents with PCOS.
aDivisionof Endocrinology and Metabolism, Department of Pediatrics, Departments of bClinical Epidemiology and Biostatistics, fPediatrics and Anesthesia, McMaster University, Hamilton,
Canada; cDepartment of Pediatrics, King Saud University, Riyadh, Saudi Arabia; dDepartment of Pediatrics, Universidad de Antioquia, Colombia; and eSt. George’s University of London,
Cranmer Terrace, London, United Kingdom
Dr Al Khalifah conceptualized and designed the study, and drafted and critically reviewed the manuscript; Dr Florez conceptualized and designed the study and
critically reviewed the manuscript; Dr Dennis designed the study and drafted and critically reviewed the manuscript; Dr Thabane designed the study and critically
reviewed the manuscript; Dr Bassilious conceptualized the study, designed the study, and critically reviewed the manuscript; and all authors approved the final
manuscript as submitted.
This systematic review has been registered with PROSPERO (CRD42015020922).
DOI: 10.1542/peds.2015-4089
To cite: Al Khalifah RA, Florez ID, Dennis B, et al. Metformin or Oral Contraceptives for Adolescents With Polycystic Ovarian Syndrome: A Meta-analysis. Pediatrics.
2016;137(5):e20154089
Study Characteristics
Four RCTs were included.39–42
Table 1 reveals the summary
of all included studies, Table 2
reveals baseline characteristics for
all outcomes, and Supplemental
Tables 7, 8, 9, and 10 reveal a
detailed summary of each study.
All studies used the NIH criteria to
diagnose PCOS. Additional inclusion
criteria identified were obesity (all
studies) and hyperinsulinism.39
All studies excluded non-PCOS
causes of hyperandrogenism
(adrenal cancer, congenital adrenal
hyperplasia, ovarian cancer, and
hyperprolactinemia), liver or kidney
disease. Three studies excluded
current or recent use of metformin
or OCP.40–42 None of the studies
FIGURE 1 described the specific ethnic origin
Study flow diagram. of the participants per intervention
arm.
treatment duration (≤6 months observed heterogeneity in our In 1 study,41 participants received
versus >6 months), use of ultrasound results. Finally, we planned to routine counseling about diet and
to document polycystic ovaries (used perform a formal assessment of exercise but no specific exercise
versus not used), and cointervention the risk of publication bias by or diet prescription was offered.
with other medications (pioglitazone, constructing funnel plots. However, The total number of patients in
spironolactone, flutamide, lifestyle there was not a sufficient number of these studies was 231 patients; 170
interventions) would explain studies to develop these graphs. were randomly assigned to receive
Menstrual regulation
Menstrual regulation
Menstrual regulation
side effects, lack of improvement, or
Total testosterone
Total testosterone
Total testosterone
Total testosterone
moving away).
Dysglycemia
Lipid profile
Lipid profile
Lipid profile
Lipid profile
Side effects
Side effects
Hirsutism
Hirsutism
Hirsutism
Hirsutism
Risk of Bias in Included Studies
Acne
BMI
BMI
BMI
BMI
All the studies were judged to be at
low risk of bias for randomization.
Norgestimate 0.25
estradiol 30 μg
estradiol 35 μg
estradiol 30 μg
estradiol 30 μg
Concealment of allocation was
Desogestrel 0.15
OCP Type and
Norethindrone1
mg, ethinyl
mg, ethinyl
mg, ethinyl
mg, ethinyl
judged to be at low risk of bias for 2
Progestin 15
Dose
1000 BID
850 BID
850 BID
in 1 study41 and another study40
revealed semiopen concealment
(eg, the metformin and placebo
groups were concealed but OCP and
lifestyle intervention groups were
Duration, mo
12–21
12–18
15–20
Age, y
15
36
4
35
21
80
N
231
34
35
43
United States
United States
Location
bias assessments.
Egypt
Total
FIGURE 4
Forest plot of comparison: 1 metformin versus OCP, outcome: 1.2 hirsutism.
FIGURE 5
Forest plot of comparison: 1 metformin versus OCP, outcome: 1.5 dysglycemia.
favoring metformin over OCP (WMD (Table 3). The quality of evidence OCP had similar impacts on hirsutism
−35.50, P = .002, 95% CI −57.45 to for all outcomes was downgraded scores, triglyceride, and HDL level.
−13.55; Supplemental Fig 10). by 2 levels for serious risk of bias This is the first systematic review
at the study design level. Further and meta-analysis for the treatment
High-Density Lipoprotein downgrading per outcome was of PCOS in adolescents comparing
Three studies39–41 revealed HDL. warranted because of imprecision metformin versus OCP. To date, there
After intervention, there was no resulting from small sample sizes and is 1 published systematic review and
statistically significant difference small event rates that did not reach meta-analysis for adults with PCOS
between groups favoring OCP over the calculated optimal information that compared metformin to OCP.49
metformin (WMD 0.71, P = .9, 95% CI size per outcome. This study pooled results from 6
−12.42 to 13.83; Supplemental studies, with 174 patients included
Fig 11). in the analysis. All the included
DISCUSSION studies lacked blinding except for 1
Adverse Events
study where the outcome assessors
Two of the authors supplemented Our search for studies of metformin were blinded. This adult-focused
adverse events when contacted.41,42 versus OCP for the treatment of PCOS systematic review revealed a similar
The adverse events were variable in adolescents yielded 4 studies that effect estimate with wider CIs
and not consistently described met our inclusion and exclusion compared with our results.49 Similar
and therefore impossible to pool. criteria. The reviewed evidence was to our results, they reported higher
El Maghraby et al42 reported derived from a very small sample menstrual bleeding (measured as
mild gastrointestinal, headache, size (170 patients) with a maximum proportion of women with regular
mastalgia, and mood change. of 149 patients contributing results menses). They did not, however,
Al-Zubeidi et al41 reported nausea, to 1 of the outcomes. The summary provide estimates in terms of mean
stomach upset, and diarrhea in of findings for all outcome measures number of menses per month. In
30% of the patients enrolled in the is shown in Table 3. Overall OCP their meta-analysis, there was no
metformin group, and no adverse treatment resulted in a modest statistically significant difference
events in the OCP group. These improvement in menstrual cycle between metformin and OCP in
are summarized in Supplemental frequency by 0.27 cycle per month terms of hirsutism scores, acne
Table 11. and mild reduction of acne scores scores, BMI, and dysglycaemia.49
by 0.3. Metformin resulted in a This is in contrast with our meta-
Publication Bias
significant BMI reduction by 4.02 analysis where we found that OCP
Although publication bias was highly compared with OCP. Subgroup resulted in slightly lower acne scores
suspected on the basis of finding analysis for BMI on the basis of among girls affected with mild
2 studies through gray literature treatment duration suggested acne and metformin lead in greater
searches, we had also identified significant weight reduction with BMI reduction, less dysglycemia
many studies that included longer metformin use. However, this prevalence, reduced total cholesterol,
adolescents and adults. Therefore, should be interpreted with caution and reduced LDL. The majority of the
we did not perform statistical testing because the analysis was derived adult patients were in the normal
for publication bias. from 4 small studies with a high risk BMI range, whereas the majority of
of bias.48 Metformin was associated the adolescent patients included in
Certainty of the Evidence
with lower risk for dysglycemia (RR = our analysis were obese. This may
Overall the quality of evidence 0.41) and improved total cholesterol suggest different treatment effects on
of the included studies was low and LDL levels. Both metformin and the basis of baseline BMI.
9
Interestingly, the majority of the challenging. It may be that patients with a decreased prevalence of
studies, including adult studies, treated with metformin have dysglycemia and improved total
did not reveal the menstrual cycle improvement in glycemic indices or cholesterol and LDL levels. However,
frequency for any patient with PCOS that OCP use is perhaps associated these estimates are derived from
started on OCP, possibly on the with worsening dysglycemia. Future very low to low quality evidence
basis of the assumption that OCP studies need to reveal incident involving small studies limited to
use is associated with regulated dysglycemia posttreatment to shed adolescents and as such the true
menstrual cycles (scheduled light on this finding. effect may be substantially different
bleeding; ie, mean of 1 cycle per The strengths of our review from that estimated in this review.
month). However, we demonstrated include the following: we performed Clinicians should be cautious advising
that the difference between a very sensitive search strategy by for or against metformin or OCP use
metformin and OCP intervention as using multiple iterations established when treating adolescents with PCOS
to how it impacts menstrual cycle with the help of a librarian with and need to include patients’ values
regularity is probably clinically expertise in systematic reviews. and preferences, as well as potential
not significant (WMD 0.27 per Additionally, we performed a gray adverse events in the decision-
month, equivalent to a difference literature search through clinical making process. Future high quality,
of 3.24 months per year). This trials registries and conferences randomized, concealed, blinded,
could be related to the definition proceedings (see Supplemental and well-powered studies are
of menstrual irregularity as most Information). Additionally, we needed to answer several questions
clinicians usually label menstrual reported on patient important for the treatment of adolescents
cycle pattern abnormality only if outcomes with emphases on with PCOS in particular relating to
the frequency of menses is less than menstrual cycle regulation. Finally, impact on hyperandrogenic features,
8 per year.4 Additionally, menstrual the choices of included outcomes dysglycemia, BMI, and improvement
cycle bleeding patterns among were based on 3 expert perceptions of cardiometabolic outcomes in this
healthy women taking OCP over (2 pediatric endocrinologists and 1 patient population.
a 12-month period may present general pediatrician) who helped
with up to a 20% amenorrhea rate shed light onto potential patient
(defined as absent menstrual bleed ACKNOWLEDGMENT
important outcomes.
for more than 2 months).44–47 We thank Mrs Neera Bhatnagar,
The observed amenorrhea could There are a number of potential from McMaster University Health
be due to poor compliance limitations in the review process. Sciences Library, for her invaluable
with OCP intake, reproductive We included studies limited to assistance in refining the search
organs immaturity, and other adolescents, and we are now strategy.
biological causes such as abnormal conducting a network meta-analysis
endometrial function. Abnormal of studies that included both
endometrial function is apparent adolescent and adult patients with
in other ways in PCOS as adult PCOS. To obtain more information ABBREVIATIONS
women with PCOS undergoing to complement incomplete outcome
CI: confidence interval
fertility treatments with proof data, we contacted the authors of
GRADE: Grading of
of ovulatory cycles still express all included studies. All of them
Recommendations
low pregnancy rates and higher responded. However, some of the
Assessment,
spontaneous miscarriages rates, outcomes sought after for this
Development, and
and menopausal women with PCOS review were not available for various
Evaluation Working
are at higher risk for endometrial reasons.
Group
cancer.18,50 Therefore, menstrual
HDL: high-density lipoprotein
cycle bleeding patterns while on
CONCLUSIONS LDL: low-density lipoprotein
treatment PCOS provides valuable
NIH: National Institutes of Health
information about endometrial We found that metformin and
OCP: oral contraceptive pill
health and should therefore be the OCP had similar results in
PCOS: polycystic ovarian
closely monitored. improvement of hirsutism scores,
syndrome
triglyceride, and HDL levels. OCP
RCT: randomized controlled trial
Moreover, our results indicate was superior for regulating menses
RR: risk ratio
that metformin use is associated regulation and improving acne
T2DM: type 2 diabetes mellitus
with a lower rate of dysglycemia. The scores. Metformin was superior for
WMD: weighted mean difference
interpretation of this association is BMI reduction and was associated
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