Human Reproduction Update, pp.

1–17, 2017
doi:10.1093/humupd/dmx039

Combined oral contraceptives

and/or antiandrogens versus insulin
sensitizers for polycystic ovary
syndrome: a systematic review
and meta-analysis
Manuel Luque-Ramírez 1,2,*, Lía Nattero-Chávez1,
Andrés E. Ortiz Flores1, and Héctor F. Escobar-Morreale1,2
1
Department of Endocrinology & Metabolism, Hospital Universitario Ramón y Cajal & Universidad de Alcalá, E-28034 Madrid, Spain
2
Diabetes, Obesity and Human Reproduction Research Group, Instituto Ramón y Cajal de Investigación Sanitaria IRYCIS & Centro de
Investigación Biomédica en Red Diabetes y Enfermedades Metabólicas Asociadas CIBERDEM, Spain

*Correspondence address. Department of Endocrinology & Metabolism, Hospital Universitario Ramón y Cajal & Universidad de Alcalá.
Carretera de Colmenar Viejo, Km 9.1, 28034 Madrid, Spain. E-mail: manuel.luque@salud.madrid.org orcid.org/0000-0002-6002-4237

Submitted on September 18, 2017; resubmitted on November 30, 2017; editorial decision on December 4, 2017;
accepted on December 6, 2017

TABLE OF CONTENTS
...........................................................................................................................
• Introduction
Review questions
• Methods
Data sources and searches
Study selection
Study population
Outcomes
Data extraction
Quality assessment
Statistical analysis
• Results
Study selection
Risk of bias of studies included in the meta-analysis
Meta-analyses of primary outcomes
Meta-analyses of secondary outcomes
• Discussion
Principal findings
Quality of evidence and applicability
Implications for practice
Implications for research
• Conclusion

© The Author(s) 2017. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology.
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 2 Luque-Ramírez et al.

BACKGROUND: Androgen excess is a key pathogenetic mechanism in polycystic ovary syndrome (PCOS), although hyperinsulinism also
contributes to androgen secretion. Therapeutic approaches for adult patients not seeking fertility include combined oral contraceptives
(COC), antiandrogens (AA) and/or insulin sensitizers, although these practices are supported by limited high-quality evidence.
OBJECTIVE AND RATIONALE: We aimed to assess the efficacy and safety of these common treatments for PCOS by conducting a
meta-analysis of RCTs with the following review questions: Which is the more appropriate therapeutic approach for hyperandrogenic
symptoms, hyperandrogenemia, and ovulatory dysfunction in adult women with PCOS not seeking fertility; What is the impact on classic
cardiometabolic risk factors of the more common treatments used in those women; Does the combination of the antiandrogenic therapy
plus metformin have any impact on efficacy or cardiometabolic profile?
SEARCH METHODS: We searched PubMed and EMBASE for articles published up to 16 September 2017. After deleting duplicates,
the abstracts of 1522 articles were analysed. We subsequently excluded 1446 articles leaving 76 studies for full-text assessment of eligibil-
ity. Of them, 43 articles were excluded. Hence, 33 studies and 1521 women were included in the quantitative synthesis and in the meta-
analyses. Meta-analyses calculated mean differences (MD), standardized mean differences (SMD), odds ratio (OR) and 95% CIs.
Heterogeneity and inconsistency across studies was assessed by χ2 test and Higgins’s I2 statistics. Quality and risk of bias of individual stud-
ies were assessed according to the Cochrane Handbook for Systematic Reviews of Interventions 5.1.0. We then used the approach
recommended by the Grading of Recommendations, Assessments, Development, and Evaluation (GRADE) group to indicate the global
quality of evidence for a selection of primary outcomes.
OUTCOMES: Regarding efficacy, the MD in hirsutism score between COC and/or AA and metformin were not significant. The exclusion
of one single study including most women with severe hirsutism yielded a significant effect in favour of COC and/or AA. When only those
studies including an AA were compared with metformin, there were significant differences favouring antiandrogenic therapy. The combin-
ation of COC and/or AA with metformin was similar to COC and/or AA therapy alone in the whole group of patients. Post-intervention
OR for the presence of regular menses favoured COC therapy. In terms of cardiometabolic impact, the MD in BMI were in favour of met-
formin. The negative effect of COC therapy on BMI was blunted by its combination with metformin. The MD in homoeostasis model
assessment of insulin resistance (HOMA-IR) were also in favour of metformin therapy compared to COC and/or AA. The combination of
COC and/or AA and metformin decreased MD in HOMA with respect to antiandrogenic therapy alone. There were no significant post-
intervention SMD in circulating glucose levels between COC and/or AA and metformin. However, adding metformin to COC and/or AA
yielded a beneficial effect on fasting glucose levels. Post-intervention OR for abnormal glucose tolerance showed no significant differences
between COC and/or AA and metformin, although after excluding studies including an AA as a comparator (without COC) a significant
effect in favour of metformin therapy was observed. There were no significant differences among therapies in lipid profile, blood pressure
or prevalence of hypertension. The global quality of evidence was very low when addressing the impact of the treatments explored on
prevalence of hypertension and lipid profiles, low in the case of hirsutism, BMI and blood pressure values, and high for endometrial protec-
tion and glucose tolerance.
WIDER IMPLICATIONS: These data provide further scientific evidence for the choice of treatment of women with PCOS. COC and
AA are more effective than metformin for hyperandrogenic symptoms and endometrial protection. Their combination with metformin
adds a positive effect on BMI and glucose tolerance.
PROSPERO CRD REGISTRATION NUMBER: CRD42016053457

Key words: antiandrogens / cardiovascular risk / combined oral contraceptives / efficacy / insulin / insulin sensitizers / metformin /
polycystic ovary syndrome / RCTs / testosterone

(Diamanti-Kandarakis and Dunaif, 2012; Wu et al., 2014). In turn,

Introduction
Polycystic ovary syndrome (PCOS) is a reproductive and endocrine
disorder that affects premenopausal women with a worldwide preva-
lence ranging from 5% to 13% under different diagnostic criteria,
almost reaching the figures for type 2 diabetes mellitus (Asuncion
et al., 2000; Sanchon et al., 2012; Yildiz et al., 2012; Bozdag et al.,
2016).
Excessive androgen biosynthesis and secretion by ovarian theca
cells is a key pathogenetic mechanism of PCOS (Wickenheisser et al.,
2006; de Medeiros et al., 2015) yet most patients presenting with
weight excess and especially those showing hyperandrogenic pheno-
types also have insulin resistance (Diamanti-Kandarakis and Dunaif,
2012; Moghetti et al., 2013). Insulin resistance and its compensatory
hyperinsulinism enhance ovarian and adrenal androgen secretion
androgen excess favours visceral fat deposition (Lim et al., 2012;
Borruel et al., 2013; Dumesic et al., 2016) and possibly adypocite
dysfunction (Luque-Ramírez et al., 2008a,b; Martínez-García et al.,
2012; Chazenbalk et al., 2013) thereby worsening the insulin resist-
ance and hyperinsulinism (Manneras-Holm et al., 2011; Moghetti
et al., 2013; Cassar et al., 2016). Hence, hyperandrogenism, dysfunc-
tional adiposity and insulin resistance contribute to increased cardio-
metabolic risk in these women (Randeva et al., 2012; Lim et al.,
2013).
Regarding classic cardiovascular risk factors, when compared
with the general female population women with PCOS show
increased prevalences of dysglycemia (Moran et al., 2010; Gambineri
et al., 2012; Joham et al., 2014a,b), dyslipidemia (Wild et al.,
2011), metabolic syndrome (Moran et al., 2010), and hypertension

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 Antiandrogenic therapy and insulin sensitizers in PCOS
(Luque-Ramírez et al., 2014; Joham et al., 2014a,b; Palomba et al.,
2015). Premenopausal women with PCOS are also at an increased
risk of endometrial cancer (Barry et al., 2014) because chronic ano-
vulation results in uterine exposure to oestrogens unopposed by
progesterone.
Accordingly, the goals of therapy in adult women with PCOS not
seeking fertility include amelioration of hyperandrogenic dermo-cosmetic
complaints, prevention of endometrial hyperplasia/adenocarcinoma,
and prevention or early treatment of cardiometabolic disturbances.
At least in theory, these goals may be accomplished by targeting both
androgen excess and/or insulin resistance (Luque-Ramirez and Escobar-
Morreale, 2015).
Lifestyle management is recommended for all patients with PCOS
(Teede et al., 2011; Legro et al., 2013; Conway et al., 2014a,b;
Goodman et al., 2015). However, although lifestyle intervention
improves body composition, cardiorespiratory fitness, and insulin
resistance (Hutchison et al., 2011; Moran et al., 2011; Harrison et al.,
2012; Haqq et al., 2015; Scott et al., 2017), the effect on hyperandro-
genemia and hirsutism is largely unsatisfactory (Moran et al., 2011,
Domecq et al., 2013). Furthermore, the impact of lifestyle modifica-
tion on long-term endometrial protection remains unknown.
Combined oral contraceptives (COC), adding an antiandrogen
(AA) in the subset of patients with severe hyperandrogenic symp-
toms or those who show a suboptimal response to COC, are effect-
ive for cosmetic complaints such as hirsutism or acne (Arowojolu
et al., 2012; Escobar-Morreale et al., 2012; Legro et al., 2013; van
Zuuren et al., 2015). COC reduce the bioavailability of circulating
free testosterone by decreasing gonadotrophin secretion and by
increasing the hepatic secretion of sex hormone-binding hormone
(Escobar-Morreale et al., 2012; Zimmerman et al., 2014). Besides,
the use of a COC confers long-term protection againsts endometrial
cancer in the general population (Collaborative Group on
Epidemiological Studies on Endometrial Cancer, 2015). Thus, for dec-
ades, COC and AA have been the first-line therapy for most adult
women with PCOS not seeking fertility (Ehrmann, 2005).
However, certain progestins and the oestrogenic component of
contraceptives may worsen insulin sensitivity in women from the gen-
eral population, particularly when given orally (Godsland et al., 1990;
Meyer et al., 2007; Sitruk-Ware and Nath, 2013). Moreover, COC
increase the relative risk of thromboembolic and cardiovascular dis-
ease (Lidegaard et al., 2012; de Bastos et al., 2014), a worrisome
issue in women already at risk of cardiovascular morbidity such as
those with PCOS (Yildiz, 2015). Therefore, insulin sensitizers have
been proposed as a safer therapeutic alternative, despite being largely
ineffective for hirsutism (Cosma et al., 2008; van Zuuren et al., 2015).
In a Cochrane review of 38 RCTs including 3495 women, metfor-
min improved ovulation rates compared with placebo, but these
results could not be confirmed in the subgroup analysis of non-obese
or obese women (Tang et al., 2012). Moreover, metformin was
slightly superior to placebo in decreasing waist-to-hip ratio, systolic
blood pressure, total testosterone levels, fasting glucose and fasting
insulin in non-obese patients (Tang et al., 2012).
In another recent meta-analysis of 12 RCTs including 608 women
(Naderpoor et al., 2016), metformin plus lifestyle modification
increased the number of menstrual cycles compared with lifestyle
plus placebo after 6 months of intervention. However, this systematic
review failed to reveal any significant impact of adding metformin to
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3
lifestyle intervention on BMI, clinical hyperandrogenism, hyperandro-
genemia, lipids, insulin sensitivity or blood pressure parameters
(Naderpoor et al., 2016).
In addition, the evidence supporting insulin sensitizers being safer
compared with COC is limited (Costello et al., 2007, Cosma et al.,
2008). A recent trial, however, showed that the addition of metfor-
min to COC may be superior to COC alone on hirsutism, BMI, body
composition, hyperandrogenemia and fasting insulin levels after 12
months of treatment (Glintborg et al., 2014a,b). Furthermore, there
are a very few RCTs comparing other insulin sensitizers, such as thia-
zolidinediones or inositols, with COC alone or their combination
(Lemay et al., 2006, Ozay et al., 2016).
Review questions
Aiming to assess the efficacy and impact on cardiometabolic risk fac-
tors of these common treatments for PCOS, we have conducted a
meta-analysis of the RCTs conducted to date with the aim of answer-
ing the following questions: Which is the more appropriate drug regi-
men for hyperandrogenic symptoms, hyperandrogenemia and
ovulatory dysfunction in adult women with PCOS not seeking fertility?
What is the impact of drugs commonly used for PCOS (COC and
AA or insulin sensitizers) on classic cardiometabolic risk factors?
Does the addition of metformin to antiandrogenic therapy have any
advantage on efficacy or cardiometabolic profiles compared with anti-
androgenic therapy alone?
Methods
We followed the recommendations of the Preferred Reporting Items for
Systematic Reviews and Meta-Analyses (PRISMA) statement for system-
atic reviews and meta-analyses (Moher et al., 2015; Shamseer et al.,
2015) and the Cochrane Handbook for Systematic Reviews of
Interventions 5.1.0 (Higgins and Green, 2011).
Data sources and searches
We searched the PubMed and EMBASE online facilities for articles pub-
lished up to 16 September 2017 introducing as MESH terms [All Fields].
Full details of the search strategy are provided in Supplementary Data.
Study selection
The reference lists of the articles selected were checked by authors to
identify any grey literature and/or studies that were missed by the pri-
mary search. The terms were combined with the Cochrane MEDLINE fil-
ter for controlled trials of interventions. The search restrictions [MESH
terms] were languages [English], species [Humans], sex [Female] and
ages [Adult]. The searches were re-run just before the final analyses and
further studies retrieved for inclusion.
Study population
Type of studies
Parallel or cross-over RCTs (only available data before wash-out period
were included) with at least 3 months of follow-up. We did not include
articles not written in English.
 4 Luque-Ramírez et al.
Participants
Women not seeking fertility with a strict diagnosis of PCOS according to
the 2012 National Institute of Health (NIH) criteria (2012) that are inclu-
sive of the earlier 1990 National Institute of Child Health and Human
Development criteria (classic phenotype consisting of women presenting
with hyperandrogenism and ovulatory dysfunction) (Zawadzki and
Dunaif, 1992), the ESHRE/American Society for Reproductive Medicine
(ASRM) definition (2004), and the Androgen Excess & PCOS Society
(AE-PCOS) criteria (Azziz et al., 2009). At least 80% of study population
had to be ≥18 years old. Hence, for studies reporting data from adoles-
cents, we estimated whether or not the 20th percentile of age of the
sample was ≥18 years old from the mean age and its SD.
Interventions
We conducted meta-analyses in studies comparing antiandrogenic ther-
apy such as COC and/or AA (cyproterone acetate, spironolactone, fluta-
mide or finasteride) alone or in combination versus insulin sensitizers
such as metformin, thiazolidinediones, and inositols, alone or in combin-
ation with antiandrogenic therapy. Concurrent use of other drugs (i.e.
corticoides) were not allowed, yet oligoelements and/or vitamins were
accepted.
Meta-analyses were conducted only for markers reported in two or
more original studies. Finally, to avoid over-representation of cases, when
several studies on the same series of patients have been published, only
the report with the larger sample size was included in the meta-analyses.
Study selection was performed independently by two investigators (L.N.
C. and A.O.F.). Disagreements were discussed and resolved by consen-
sus or by arbitration with an author not involved in the search of the lit-
erature (M.L.-R).
Outcomes
Efficacy
The primary outcomes were hirsutism (hirsutism score and/or hair diam-
eter) and menstrual regularity. The secondary outcomes were acne
degree, total testosterone, free testosterone, free androgen index (FAI),
androstenedione and dehydroepiandrosterone-sulphate concentrations.
Cardiometabolic risk factors
The primary outcomes were BMI, fasting glucose, plasma glucose 2 h after
a standard oral glucose tolerance test (OGTT), insulin sensitivity [insulin
sensitivity index (ISI) from OGTT, quantitative insulin sensitivity check
index (QUICKI) or M-value during euglycemic hyperinsulinemic clamp],
homoeostasis model assessment of insulin resistance (HOMA-IR), fre-
quency of glucose tolerance abnormalities, low density-lipoprotein (LDL)
cholesterol, high density-lipoprotein (HDL) cholesterol, triglycerides, sys-
tolic and diastolic blood pressure, frequency of arterial hypertension.
The secondary outcomes were waist circumference, waist-to-hip ratio
(WHR), fasting insulin, area under the curve of insulin and glucose during
the OGTT, fasting glucose/insulin ratio, total cholesterol.
Data extraction
M.L.-R. extracted the following data from the retrieved studies included
in the meta-analysis: authors’ names, publication date, country, sample
size, diagnostic criteria for PCOS, study design and duration, intervention,
mean and SD for continuous variables and events for dichotomuous vari-
ables of pre-specified outcomes. Data extraction is fully described in
Supplementary Data.
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Quality assessment
Two authors (M.L.-R. and H.F.E.-M.) independently assessed the risk of
bias of individual studies using the Cochrane Collaboration tool for asses-
sing risk of bias (Higgins and Green, 2011) (see also Supplementary Data).
Disagreements over the risk of bias were resolved by consensus or arbitra-
tion by L.N.C. when necessary. For each entry, bias was judged ‘low risk’,
‘high risk’ or ‘unclear risk’. A risk of bias graph plotting the proportion
of studies with each of the judgments and a risk of bias summary graph
plotting all of the judgments in a cross-tabulation of study by entry, were
generated using Review Manager version 5.3 (RevMan 5.3, Copenhagen:
The Nordic Cochrane Centre, The Cochrane Collaboration, 2014).
Then, in order to address the quality of evidence derived from our
systematic review for primary outcomes separately, after assessing
study limitations (risk of bias) as outlined above, we used the Grading of
Recommendations, Assessments, Development, and Evaluation (GRADE)
system (Guyatt et al., 2008; Andrews et al., 2013) with the requirements
specified in the GRADE Handbook for grading the quality of evidence for
systematic reviews (http://gdt.guidelinedevelopment.org/app/handbook/
handbook.html). Results were summarized using the GRADEpro GDT free
online application (https://gradepro.org, last accessed 30 October 2017).
Statistical analysis
Meta-analyses were performed using the RevMan 5.3 programme (Copenhagen:
The Nordic Cochrane Centre, The Cochrane Collaboration, 2014).
Whenever possible we calculated post-intervention standardized mean
differences (SMD) statistics for continuous variables as a measure of
effect size, in order to reduce the variability derived from the differ-
ences in the methodology of outcome assessment used in the different
studies. We also calculated 95% CIs of the SMD.
In order to interpret reported units of SMD we transformed the effect
back to expected change in percentile rank of every outcome for an aver-
age women with PCOS on one arm of treatment compared with the
other arm of treatment using the Cohen’s U3 index. In some studies,
changes from baseline differences were the only available data. Change
scores address the same intervention effects as MD do using final mea-
surements. Therefore, there is no reason in statistical terms for not com-
bining in a single meta-analysis studies in which outcomes are reported as
change-from-baseline scores with studies that report final measurement
outcomes, as long as MD instead of SMD are used (Higgins and Green,
2011). Hence, in some cases both post-intervention scores and differ-
ences in the changes observed in the scores were used in the same
meta-analysis, and MD and 95% CI were reported. For clarity, individual
studies reporting change in scores were appropriately highlighted in the
different meta-analyses.
Aiming to provide a straightforward interpretation of the actual differ-
ent effect among treatments, forest plots of continuous outcomes are
shown as absolute differences among them and arrows beneath graphs
show if the direction of the effect favoured one or other treatment. The
figures below the horizontal axis represent the magnitude of that effect.
Heterogeneity and inconsistency across studies was assessed by χ2 test
and Higgins’s I2 statistics. I2 > 50% was considered as a substantial het-
erogeneity. Fixed-effect models were used for variables with low to mod-
erate heterogeneity and random-effect models were applied to variables
showing substantial heterogeneity. In random-effect models, the SD of
underlying effects across studies was estimated as Tau2. For dichotomou-
ous data, results for each study were expressed as odds ratios (OR) with
95% CI and combined for meta-analysis using the Mantel–Haenszel fixed-
effect method.
When the meta-analyses included 10 or more studies, we estimated
evidence dissemination bias by funnel plot asymmetry and Egger’s
 Antiandrogenic therapy and insulin sensitizers in PCOS
regression tests using the free software ‘Meta-Essentials: Workbooks for
meta-analysis’ version 1.0. (http://www.erim.eur.nl/research-support/
meta-essentials).
When data were available, separate meta-analyses were performed for
non-obese and overweight patients, and meta-analysis were repeated
after excluding studies in which AA were used as single drugs and not in
combination with COCs.
Results
Study selection
Fig. 1 shows the PRISMA flow chart, from identification of studies to
meta-analysis. After deleting duplicates, the abstracts of 1522 articles
were analysed. We subsequently excluded 1446 records on the basis
of the title or abstract because these articles were undoubtedly not
relevant for the present review.
The full-text of the remaining 76 articles was assessed for eligibility.
Of them, 43 articles were excluded: 10 studies described non-
randomized trials (Mitkov et al., 2005; Aghamohammadzadeh et al.,
2010; Hu et al., 2010; Fabregues et al., 2011; Kebapcilar et al., 2011;
Lazaro et al., 2011; Minozzi et al., 2011; Naka et al., 2011; Orbetzova
et al., 2011; Suvarna et al., 2016), 10 studies applied interventions dif-
ferent than those analysed here (Ibañez and de Zegher, 2004, 2005;
Ibanez et al., 2006, 2007, 2008, 2010; Hadziomerovic-Pekic et al.,
Figure 1 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow chart for a systematic review and meta-analysis of
combined oral contraceptives and/or antiandrogens versus insulin sensitizers for polycystic ovary syndrome.
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2010; Mazza et al., 2014; Shayan et al., 2016; Wang et al., 2016), nine
studies included the same series of participants already collected in
another study not reporting any new outcome of interest for the
review (Morin-Papunen et al., 2003a, b; Hutchison et al., 2008;
Luque-Ramírez et al., 2009a, b; Teede et al., 2010; Luque-Ramirez
and Escobar-Morreale, 2011; Luque-Ramírez et al., 2011; Glintborg
et al., 2014a, b, 2015, 2017), in four studies over 20% of the total
study population consisted of adolescent participants (Ibanez and De
Zegher, 2003; Allen et al., 2005; Ibañez et al., 2005; Al-Zubeidi and
Klein, 2015), two studies did not report outcomes of interest for the
meta-analysis (Ibanez et al., 2011; Cakiroglu et al., 2013), two were
only published as a congress abstract (Andreeva et al., 2016; Moretti
et al., 2016), in one study the patients had been followed for only 1
month (Sahin et al., 2004), and one study was a cross-over trial and
outcomes before crossing were not reported (Dardzinska et al.,
2014). We excluded another two articles after not obtaining any
response to our query for data clarification from the authors (see
Supplementary Data). One of them (Diri et al., 2016) reported dis-
persion measures as a structural equation modelling. The other
(Mhao et al., 2016) did not detail PCOS criteria and participant’s
ages. Finally, two RCTs could not be included in any meta-analysis
because the particular interventions analysed in them were not
addressed by any other trial (Lemay et al., 2006; Ozay et al., 2016).
Hence, 33 studies were included in the quantitative synthesis and
in the different meta-analyses (Morin-Papunen et al., 2000, 2003a, b;
 6 Luque-Ramírez et al.
Elter et al., 2002; Harborne et al., 2003; Ganie et al., 2004, 2013;
Cibula et al., 2005; Lv et al., 2005; Rautio et al., 2005; Gambineri
et al., 2006; Meyer et al., 2007; Luque-Ramírez et al., 2007a, b, c,
2008a, b, 2009a, b; Ozgurtas et al., 2008; Wu et al., 2008; Bilgir
et al., 2009; Fruzzetti et al., 2010; Kebapcilar et al., 2010; Essah et al.,
2011; Kilic et al., 2011; Panidis et al., 2011; Wei et al., 2012; Moro
et al., 2013; Muneyyirci-Delale et al., 2013; Christakou et al., 2014;
Glintborg et al., 2014a, b; Kaya et al., 2015; Feng et al., 2016;
Mehrabian et al., 2016; Alpañés et al., 2017) (Supplementary
Table SI).
Risk of bias of studies included in the meta-
analysis
A plot of the distribution and a summary table of each of the items for
assessing the risk of bias are shown in Supplementary Fig. S1. The main
reasons for high risk of bias were no blinding of participants, and per-
sonnel (performance bias) and selective reporting (reporting bias). It is
also worth noting that more than 50% of studies had an unclear or
high risk of biased allocation to interventions likely related to inad-
equate/unclear concealment prior to assignment. A detailed descrip-
tion of potential sources of bias is shown in the Supplementary Data.
Meta-analyses of primary outcomes
Efficacy
Hirsutism. For the meta-analysis of hirsutism we included only studies
with at least a 6-month follow-up, considering that this is the physio-
logical length of the terminal hair cycle and a shorter duration of inter-
ventions was unlikely to produce any noticeable result (Escobar-
Morreale et al., 2012). The MD between COC and/or AA and metfor-
min were not significant [n = 273; MD (95% CI): −1.08 points (−2.4,
0.2); Overall effect: Z = 1.63, P = 0.10; Heterogeneity: τ2 = 2.93, χ2 =
41.62, df = 9, P < 0.00001; I2 = 78%]. We observed similar results
when restricting the analysis to the four studies with 12-month of
follow-up, or when excluding studies using COC without AA (data not
shown).
However, one particular study that included women with severe hir-
sutism showed contradictory results, with a greater degree of reduc-
tion in hirsutism score in those patients on metformin despite mean
hair diameters being reduced to a similar degree in both arms of treat-
ment, and those women on COC had a greater reduction at several
anatomical sites such as mid-thigh or forearm (Harborne et al., 2003).
After excluding the Harborne et al. (2003) study, the meta-analysis
showed a larger decrease in the hirsutism score with COC and/or AA
compared with metformin (Fig. 2A). Moreover, when studies including
an AA with or without COC where compared with metformin, there
were significant differences favouring the antiandrogenic therapy too
(Fig. 2B). There were enough data to conduct the meta-analysis separ-
ately in PCOS patients with weight excess (three studies, 155 patients)
yet MD in hirsutism score between treatments were not significant in
this subgroup of patients (data not shown).
The addition of metformin to COC and/or AA (three studies, 196
patients) was similar to COC and/or AA therapy alone on the hirsut-
ism score, regardless of the presence or absence of weight excess
(data not shown).
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Endometrial protection. Post-intervention OR for the presence or
absence of regular menses favoured COC therapy over metformin in
the meta-analysis of three studies that reported such data (Fig. 2C).
Two studies (102 patients) reported this outcome as length of men-
strual cycles (days). The trend towards shorter cycles in women trea-
ted with COC compared to those on metformin did not reach
statistical significance [MD (95% CI): −25.8 days (−50.3, 0.7); χ2: 2.0,
P = 0.37; I2: 0%]. In three studies (213 patients), data were reported
as number of cycles per 6 or 12 months, again not showing statistic-
ally significant differences [SMD (95% CI): 0.27 (0.00, 0.54);
Heterogeneity: χ2: 2.1, P = 0.36; I2: 3%]. Two studies compared AA
alone with AA plus metformin on the number of cycles per 6 or 12
months (150 patients), but no significant differences among treat-
ments were found [SMD (95% CI): −0.37 (−0.90, 0.15); τ2: 0.1,
Heterogeneity: χ2: 2.1, P = 0.15; I2: 51%].
Cardiometabolic risk factors
BMI. The reduction in BMI with metformin was larger than with
COC and/or AA therapy (Fig. 3A), and even greater after excluding
those studies where the comparator was an AA alone (15 studies,
805 patients) [MD (95% CI): −0.51 kg/m2 (−0.89, −0.13); χ2: 19.8,
P = 0.14; I2: 29%]. In the separate meta-analysis of non-obese (five
studies, 265 patients) and overweight (six studies, 244 patients) sub-
groups, the MD between treatments was not significant. Moreover,
the addition of metformin to COC and/or AA on BMI also benefited
patients by inducing a larger decrease in BMI (Fig. 3B). In the meta-
analysis comparing BMI in women submitted to treatment with COC
and/or AA or combination of COC and/or AA plus metformin, sig-
nificant publication bias was found (Supplementary Fig. S2).
Insulin resistance and glucose tolerance. Metformin resulted in smaller
HOMA-IR values compared to COC and/or AA (Fig. 4A), and that
effect was virtually identical after excluding studies in which AA were
administered as single therapy (nine studies, 538 patients) [MD (95%
CI): −0.46 (−0.60, −0.31); χ2: 20.8, P = 0.05; I2: 42%].
The meta-analysis of the subgroup of non-obese women (three
studies, 195 patients) sustained these results [SMD (95% CI): −0.67
(−0.93, −0.41), Cohen’s U: −19%; χ2: 4.0, P = 0.41; I2: 0%]. The
addition of metformin to COC and/or AA also decreased HOMA
with respect to antiandrogenic therapy alone (Fig. 4B). However, we
found evidence for publication bias in some of the studies included in
the meta-analysis (Supplementary Fig. S2).
On the contrary, the meta-analysis of the differences between
COC and/or AA and metformin on insulin sensitivity did not show
statistically significant differences (Fig. 4C). However, after excluding
the studies in which AA were used without COC, metformin
increased post-intervention insulin sensitivity compared with COC ±
AA (four studies, 151 patients), [SMD (95% CI): 0.45, Cohen’s U:
17%; χ2: 0.31, P = 0.99, I2 = 0%]. We did not find significant differ-
ences in the meta-analyses of weight subgroups. The addition of met-
formin to antiandrogenic therapy did not add any benefit on insulin
sensitivity (Fig. 4D). The meta-analysis of the subgroup of overweight
women (two studies, 56 patients) also did not show significant differ-
ences (data not shown).
There were no statistically significant post-intervention SMD in
fasting glucose levels between COC and/or AA and metformin
(Fig. 5A). After excluding studies with AA alone as a comparator,
 Antiandrogenic therapy and insulin sensitizers in PCOS 7

Figure 2 Meta-analysis of primary efficacy outcomes. Forest plots of hirsutism score show absolute differences among therapies, and
arrows beneath graphs show if the direction of the effect favoured one or other treatment. The diamond represents the mean effect size and
95% CI, and the figures below the horizontal axis represent the magnitude of the effect. Panel A, mean differences (MD) between combined
oral contraceptives (COC) and/or antiandrogen (AA) therapy and metformin. Panel B, MD between those studies including an AA ± COC
compared to metformin. Panel C, odds ratio for regular menses comparing COC ± AA therapy versus metformin. *Differences in the change
of scores.

there were no significant differences (six studies, 269 patients, data
not shown), as was the case in the separate analyses of non-obese
women (two studies, 62 patients, data not shown) and overweight
women (two studies, 55 patients, data not shown). However, add-
ition of metformin to COC and/or AA yielded a beneficial reduction
in fasting glucose concentrations with respect to COC and/or AA
therapy alone (Fig. 5B). Such a beneficial effect was found in the sub-
group of non-obese women in combined therapy (three studies, 137
patients) [SMD (95% CI): −0.49 (−0.82, −0.17), Cohen’s U: −19%;
χ2: 2.4, P = 0.49; I2: 0%], but not in overweight women (two studies,
56 patients, data not shown).
The meta-analysis of plasma glucose concentrations measured
after 120 min of a standard OGTT showed no significant differences
between COC and/or AA and metformin therapies (Fig. 5C). The
exclusion of the studies administering AA without COC did not
change these results (two studies, 69 patients, data not shown). The
combination of metformin with an antiandrogenic therapy did not
yield any advantage either (Fig. 5D).

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 8 Luque-Ramírez et al.

Figure 3 Meta-analysis of effect differences on BMI. Forest plots of BMI show absolute differences among therapies, and arrows beneath graphs
show if the direction of the effect favoured one of other treatment. Panel A, MD between COC and/or AA therapy versus metformin. Panel B,
MD between COC and/or an AA versus the same antiandrogenic therapy plus metformin. *Differences in the change of scores.

Finally, the post-intervention OR for abnormal glucose tolerance
showed no significant differences between COC and/or AA and
metformin (Fig. 5E) although, after excluding studies administering
AA without COC, a statistically significant effect against COC ther-
apy was observed [three studies, 93 patients, OR (95% CI): 4.5
(1.4–14.1); overall effect Z = 2.59, P = 0.01; Heterogeneity χ2 = 1.4,
df = 2, P = 0.51; I2 = 0%]. The meta-analysis of the only two studies
(55 patients) that evaluated this outcome in overweight women did
not show significant differences between therapies (data not shown).
Another two studies (150 patients) comparing an AA (without COC)
with the same AA plus metformin showed no differences in the OR
for abnormal glucose tolerance (data not shown).
Lipid profile. We found no differences in the impact of COC and/or
AA or metformin on LDL-cholesterol, HDL-cholesterol or triglycer-
ides levels (Supplementary Fig. S3). The exclusion of the studies
administering AA without COC did not change these results. The
separate meta-analyses of overweight women did not show signifi-
cant MD among treatments in LDL-cholesterol levels (two studies,
137 patients, data not shown), HDL-cholesterol (three studies, 163
patients, data not shown) or triglycerides (three studies, 163 patients,
data not shown). Adding metformin to COC and/or AA was no bet-
ter than COC and/or AA therapy alone on LDL-cholesterol, HDL-
cholesterol levels (12 studies, 539 patients), or triglycerides (12 stud-
ies, 527 patients), in any group of women (data not shown).

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 Antiandrogenic therapy and insulin sensitizers in PCOS 9

Figure 4 Meta-analysis of effect differences on insulin resistance. Forest plots of homoeostasis model assessment of insulin resistance (HOMA-IR)
and insulin sensitivity show absolute differences among therapies, and arrows beneath graphs show if the direction of the effect favoured one of
other treatment. Panel A, MD between COC and/or AA therapy and metformin in HOMA. Panel B, MD between COC and/or AA therapy and
the same therapy plus metformin in HOMA. Panel C, MD between COC and/or therapy and metformin in insulin sensitivity. Panel D, MD between
COC and/or AA therapy and the same therapy plus metformin on insulin sensitivity. *Differences in the change of scores.

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 10 Luque-Ramírez et al.

Figure 5 Meta-analysis of effect differences on glucose levels and frequency of dysglycemia. Forest plots of plasma glucose show absolute differ-
ences among therapies, and arrows beneath graphs show if the direction of the effect favoured one of other treatment. Panel A, standard mean dif-
ferences (SMD) between COC and/or AA and metformin in fasting glucose levels. Panel B, MD between COC and/or AA and the same therapy

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 Antiandrogenic therapy and insulin sensitizers in PCOS
plus metformin in fasting glucose levels. Panel C, SMD between COC and/or AA and metformin in plasma glucose-120 min after a standard oral glu-
cose tolerance test (OGTT). Panel D, SMD between COC and/or AA and the same therapy plus metformin in plasma glucose-120 min after an
OGTT. Panel E, odds ratio (OR) for abnormal glucose tolerance comparing COC ± AA therapy versus metformin. *Differences in the change of
scores.
Blood pressure. No MD were observed in systolic and diastolic blood
pressure between metformin and COC and/or AA (Supplementary
Fig. S4), even after excluding the studies administering AA as single
drugs (data not shown). The meta-analysis of systolic blood pressure
in overweight women (two studies, 138 patients) did not show signifi-
cant differences either (data not shown). The addition of metformin
to COC and/or AA did not show any advantage over COC and/or
AA alone on systolic blood pressure or diastolic blood pressure (four
studies, 264 patients, data not shown). Also, the two studies that
addressed the OR for hypertension of COC and/or AA over metfor-
min did not show statistically significant differences (data not shown).
Meta-analyses of secondary outcomes
As a general rule, COC or/and AA treatment decreased circulating andro-
gen concentrations more profoundly than metformin (Supplementary
Table SII) and the combination of metformin with COC and/or AA ther-
apy did not result in any additional effect on hyperandrogenemia but in
androstenedione levels. There were no statistically significant MD between
treatments on waist circumference nor was there any effect of the addition
of metformin to COC and/or AA on this outcome (Supplementary
Table SIII). We observed a larger reduction in WHR with metformin com-
pared with COC and/or AA but only in non-obese women, and no differ-
ences were observed in other comparisons and combined therapy did not
provide any advantage over each drug alone (data not shown). Metformin
was superior to COC and/or AA in decreasing fasting insulin con-
centrations and the area under the curve of insulin during an OGTT
(Supplementary Table SIII), but these results were not confirmed in
the separate meta-analysis of overweight women (data not shown).
Combined therapy was not different to COC and/or AA alone on
insulin levels either (data not shown). Metformin increased the fast-
ing glucose to insulin ratio to a greater extent than COC and/or
AA when considering all patients as a whole irrespective of weight
excess, and in the studies addressing combined therapy (Supplementary
Table SIII), but not in the separate meta-analysis of overweight women
(data not shown).
Discussion
Principal findings
Our systematic review collecting the best evidence available to date sug-
gests that antiandrogenic therapy, namely COC and AA, was superior
to insulin sensitizers for low-to-moderate hyperandrogenic symptoms,
hyperandrogenemia, and endometrial protection in women with PCOS
not pursuing pregnancy. A summary of the most relevant findings is
shown in Fig. 6. Addition of metformin to antiandrogenic therapy did
not increase efficacy. Regarding cardiometabolic outcomes, metformin
therapy improved BMI, insulin sensitivity, and glucose tolerance and, its
combination with antiandrogenic therapy provided additional benefits on
BMI, fasting glucose levels, and insulin sensitivity with respect to
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11
administration of COC and/or AA alone. Finally, we observed no differ-
ences among the pharmacologic approaches analysed here on lipid and
blood pressure profiles.
Two meta-analyses addressing the different effects of these therap-
ies on women with PCOS have been published (Costello et al., 2007;
Cosma et al., 2008). Our present study, albeit conducted almost a
decade later and including a much larger number of studies in which
PCOS had been diagnosed strictly, shows no major disagreements
with these earlier meta-analyses.
Quality of evidence and applicability
The quality of evidence ranged from very low to high according to
the GRADE system. Table I shows a summary of the quality of evi-
dence grades for selected primary outcomes. Quality of evidence
was very low for prevalence of hypertension and lipid profiles, low
for hirsutism, BMI and blood pressure values, and high for endomet-
rial protection and glucose tolerance. Several factors reduced the
quality of evidence, but the most important were limitations of the
original studies derived from the lack of blinding of both participants
and research personnel, and from unexplained heterogeneity
between studies in estimates of the treatment effects.
The potential weaknesses of our meta-analyses derived, therefore,
from the original limitations of the individual RCTs that have been
detailed throughout the manuscript. All but one of the RCTs did not
stress the need for dieting and/or exercising during the follow-up,
despite lifestyle changes being recommended at the initial visit in
many of them. This may have influenced cardiometabolic outcomes
and, together with the lack of blinding in all but one study, possibly
biased the reported findings. It is also difficult to explain how the only
RCT showing a large effect of metformin on hirsutism patient’s self-
assessments did not find any significant difference with the COC in
objective measurements of hair diameter (Harborne et al., 2003).
Drug compliance was not stressed during the intervention in most
studies either, a matter of importance for women on metformin con-
sidering the relatively large drop-out rate observed among the
women taking this drug in several trials (Morin-Papunen et al., 2000;
Ganie et al., 2004, 2013; Luque-Ramírez et al., 2007a,b,c; Kilic et al.,
2011; Moro et al., 2013; Christakou et al., 2014; Glintborg et al.,
2014a,b; Alpañés et al., 2017). Moreover, the duration of interven-
tions was possibly too short in many studies to observe actual
changes in hirsutism or certain metabolic outcomes such as dysglyce-
mia. Finally, the present results only apply to adult patients and
should not be extrapolated to adolescents with PCOS, for whom
treatment strategies based on quality evidence are unfortunately lack-
ing (Al Khalifah et al., 2016).
Implications for practice
Even although none of the current clinical guidelines for the manage-
ment of PCOS support the use of metformin as first-line drug for
hyperandrogenic symptoms or endometrial protection (Fauser et al.,
 12 Luque-Ramírez et al.

Figure 6 Summary of relevant findings in meta-analysed outcomes. The yellow area includes outcomes showing statistically significant differences
in favour of antiandrogenic therapy (COC ± AA) when compared with metformin therapy. The blue area shows outcomes significantly different in
favour of metformin therapy compared with antiandrogenic therapy. The green area (centre) depicts the outcomes showing statistically significant
differences in favour of antiandrogenic therapy plus metformin compared with antiandrogenic therapy alone. Boldface typography highlights primary
outcomes whereas regular typography is used for secondary outcomes. AUC: area under curve.

Table I Quality of evidence of selected primary outcomes according to the GRADE Working Group.

Outcome Certainty assessment Quality of

.........................................................................................................................................
evidence
Risk of bias Inconsistency of Indirectness of Imprecision Others
results evidence considerations
.............................................................................................................................................................................................
Hirsutism Serious limitations No important Direct Not None Low
important ⊕⊕○○
Menstrual dysfunction Serious limitations No important Direct Not Large magnitude of effect High
important ⊕⊕⊕⊕
BMI Serious limitations No important Direct Not Publication bias Low
important ⊕⊕○○
Abnormal glucose Serious limitations No important Direct Not Large magnitude of effect High
tolerance important ⊕⊕⊕⊕
Lipid profile Serious limitations Very important Direct Not None Very low
important ⊕○○○
Blood pressure Serious limitations Important Direct Not None Low
important ⊕⊕○○
Hypertension Serious limitations Very important Direct Very None Very low
Important ⊕○○○

The table was generated using the Grading of Recommendations, Assessments, Development, and Evaluation (GRADEpro) GDT free online application (https://gradepro.org/,
last accessed 30 October 2017).
Quality of evidence: High quality means that further research is very unlikely to change our confidence in the estimate of effect; moderate quality means that further research
is likely to have an important impact on our confidence in the estimate of effect and may change the estimate; low quality means that further research is very likely to have an
important impact on our confidence in the estimate of effect and is likely to change the estimate; very low quality means that we are uncertain about the estimate.

2012; Legro et al., 2013; Conway et al., 2014a,b), a recent survey of
clinical practices for the management of PCOS among European
endocrinologists brought to light that this insulin sensitizer was the
most commonly prescribed drug in patients with the syndrome
(Conway et al., 2014a,b). Furthermore, data from US female resi-
dents with private health insurance coverage suggest that over 45%
of women with PCOS on COC therapy were taking metformin con-
comitantly, despite only 15% of them having a claim for diabetes
(Bird et al., 2013). The rationale behind the use of insulin sensitizers
in patients with PCOS, particularly metformin, appears to be their
presumed superiority over COC and/or AA in terms of amelioration
of cardiometabolic risk factors (Goodman et al., 2015), in spite of the

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 Antiandrogenic therapy and insulin sensitizers in PCOS
fact that a negative impact of COCs on the cardiovascular risk factors
of women with PCOS still needs to be demonstrated by actual scien-
tific evidence and the long-term cardiovascular effects of these drugs
are currently unknown.
In contrast, our present data provide the best available evidence to
date to support therapeutic decisions at the point of care. According to
our analyses, antiandrogenic therapy appeared to be the best choice for
symptoms of hyperandrogenism and endometrial protection. Since
women with PCOS seeking health care usually show more severe phe-
notypes than those in the general population (Ezeh et al., 2013; Luque-
Ramirez et al., 2015; Lizneva et al., 2016), COC ± AA should possibly
remain as first-line therapy for most adult patients not seeking fertility.
Moreover, metformin use was not supported by our results for any
PCOS-related symptom aside from weight reduction. The combination
of COC ± AA and metformin, however, may be indicated in women
with weight excess and in those presenting with insulin resistance and/
or abnormal glucose tolerance.
Implications for research
The main implication for future research of the present comprehensive
meta-analysis is that PCOS management remains in urgent need of long-
term high-quality studies including large samples of women with the
syndrome. In this regard, only multi-centre, preferably multi-national,
unbiased randomized studies many answer the currently unsolved ques-
tions such as: Why do RCTs only show a small effect of COC on hirsut-
ism when clinical experience appears to say the opposite? What is the
actual impact of COC administration on the development of dysglyce-
mia? Does metformin, alone or in combination with COC, prevent the
development dysglycemia in PCOS patients at risk? Do these drugs
work differently in lean patients and women with overweight or obesity?
Does the response to these drugs differ across the spectrum of PCOS
phenotypes included in current diagnostic classifications?
Such studies, which are justified by the very high prevalence of
PCOS worldwide, would definitely need international networks, a
much greater involvement of health authorities and, possibly,
industry-sponsored research.
Conclusion
Our present results provide scientific evidence to guide the pharmaco-
logic treatment of women with PCOS not seeking immediate fertility.
COC and AA are more effective than metformin for hyperandrogenic
symptoms and endometrial protection. Their combination with met-
formin may, however, provide an additional beneficial effect on BMI
and glucose tolerance.
Supplementary data
Supplementary data are available at Human Reproduction Update online.
Authors’ roles
L.N.C., A.O.F., and M.L-R. searched and reviewed the literature and
revised the article critically for important intellectual content. L.N.C.
and A.O.F. selected articles. M.L.-R. arbitrated disagreements in the
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13
selection of articles, analysed the data and wrote the final version of
the manuscript. H.F.E.-M. contributed to study conception and design,
analysed the data, and revised the article critically for important intel-
lectual content. All authors approved the final version of the article
and take full responsibility for the accuracy of its content.
Funding
Supported by Grants PI1400649, PI1501686 and PIE1600050 from
Instituto de Salud Carlos III, Spanish Ministry of Economy and
Competitiveness. Supported in part by European Regional Development
Fund ERDF from the European Comission. Centro de Investigación
Biomédica en Red Diabetes y Enfermedades Metabólicas CIBERDEM
and instituto Ramón y Cajal de Investigación Sanitaria IRYCIS are also
initiatives of Instituto de Salud Carlos III.
Conflict of interest
The authors declare that they do not have any financial, personal, or
professional competing interest relevant to this work.
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