Middle East Fertility Society Journal (2015) 20, 131137

Middle East Fertility Society

Middle East Fertility Society Journal

www.mefsjournal.org
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ORIGINAL ARTICLE

Randomized controlled trial of the eects of

metformin versus combined oral contraceptives
in adolescent PCOS women through a 24 month
follow up period
a,d a,c b,d e,*
H.A. El Maghraby , T. Nafee , D. Guiziry , A. Elnashar

a
Department of Obstetrics and Gynecology, Faculty of Medicine, University of Alexandria, Egypt
b
Department of Clinical Pathology, Faculty of Medicine, University of Alexandria, Egypt
c
Institute of Science and Technology in Medicine, Keele University Medical School, UK
d
Alexandria IVF/ICSI Centre, El-Hedaya, Alexandria, Egypt
e
Department of Obstetrics and Gynecology, Benha University Hospital, Egypt

Received 18 October 2014; accepted 19 October 2014

Available online 27 November 2014

KEYWORDS Abstract Objective: To compare metformin and combined oral contraceptive pill (COC) effects
Adolescent; over 24 months in adolescent PCOS. Design: Randomized controlled study. Setting: Alexandria
Polycystic ovary; ICSI centre. Patients: 117 adolescent girls with PCOS, were randomized to: group A (n = 40): met-
Insulin resistance; formin, group B (n = 40): COC, and group C (n = 39): control. Interventions: Group A: received
Metformin; metformin, group B: received combined oral contraceptives. Main outcome measures: Improvement
Combined oral contraceptive in cycle rhythm and hirsutism. Results: In group B a signicant decline in serum testosterone
reached the lowest value by the end of the second year (0.7 0.2 versus 1.3 0.5 lg/ml). By
the end of the study, group A showed a signicant decline in fasting (18.6 3.0
10.0 3.0 lIU/ml) and after-load insulin levels (126 4364 15 lIU/ml) with a signicant rise
in glucose/insulin ratio (GIR) from 4.1 0.3 to 4.6 0.5. Group B showed a signicant rise in
fasting and after-load insulin (from 15.0 3.0 lIU/ml and 103.0 91.0 lIU/ml to 19.0 4.0
and 187.0 22.0 lIU/ml, respectively) and GIR dropped signicantly from 4.4 0.2 to
3.1 0.3. Metformin was associated with a signicant loss of weight from 87.0 6.0 to
72.0 0.5 kg while COC was associated with a non-signicant gain in weight (from 84.0 6.0
to 91.0 9.0 kg). Conclusions: Metformin and COC have comparable therapeutic effectiveness
on cycle regularity and hirsutism. Metformin was associated with a signicant improvement in met-

* Corresponding author at: Faculty of Medicine, University of Benha,

24 Gomhoria St., Mansura, Egypt. Tel.: +20 1066934749.
E-mail address: elnashar53@hotmail.com (A. Elnashar).
Peer review under responsibility of Middle East Fertility Society.

Production and hosting by Elsevier

http://dx.doi.org/10.1016/j.mefs.2014.10.003
1110-5690 2014 The Authors. Production and hosting by Elsevier B.V. on behalf of Middle East Fertility Society.
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).
132
abolic syndrome, while COC was associated with a deterioration of metabolic syndrome.
2014 The Authors. Production and hosting by Elsevier B.V. on behalf of Middle East Fertility Society.
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-
1. Introduction
Adolescent polycystic ovary syndrome (PCOS) represents a
distinct clinical variant of a notoriously heterogeneous disor-
der. The condition affects a substantial number of adolescent
girls with reportedly increasing incidence, probably in associa-
tion with increasing prevalence of childhood obesity [1].
Although evidence is contradictory, it is likely that adolescent
PCOS runs a progressive course with the potential to develop
full-blown picture of adult PCOS, and the subsequent serious
long-term health sequelae associated with the metabolic syn-
drome [2]; hence, the importance of correcting the underlying
metabolic derangement in these young women. The newly rec-
ognized association between PCOS, particularly adolescent
form, and depressive disorders [3], lower health-related quality
of life (HRQL) [4] and systemic low grade inammation [5]
emphasizes the importance of a holistic approach in
management.
The therapeutic goals in the management of adolescent
PCOS women should, therefore, be symptomatic and prophy-
lactic; aiming at restoration of body weight, cycle regulation,
reducing signs of hyperandrogenism, and prevention of long-
term health hazards. Treatment of this particular group of
young patients should consider safety, acceptability, compli-
ance, and achievement of initial therapeutic goals.
The protracted course of the syndrome, spanning most of
the reproductive life of the women involved, with possible
long-term sequelae [6], necessitates intermediate and long-term
monitoring of the course of various components of the syn-
drome, and the effect of various therapeutic lines on them
[7,8]. There are few studies comparing contraceptive pills and
metformin in adolescents. One study conducted on 35 obese
adolescents with short-term follow up showed that adolescents
with PCOS treated with metformin or COC experienced simi-
lar benecial outcomes including reduction in androgen levels,
weight loss, and increased insulin sensitivity [9]. The longest
period of follow up in one recent Cochrane review of random-
ized controlled trials, which included a total of 104 adult
PCOS women, was 12 months. The meta-analysis showed that
there was no difference in the therapeutic effectiveness between
metformin and COC on hirsutism and acne, but metformin
treatment resulted in a reduction in fasting insulin and lower
triglyceride levels than COC [10,11].
The choice of medical therapy may also depend on the clin-
ical presentation. Oral contraceptives (COC) are a good option
when acne and hirsutism are the principal complaints. The use
of long-term insulin sensitizers, particularly metformin, for
these purposes in adolescents is the subject for an inter-disci-
plinary debate. A non-randomized study showed that metfor-
min treatment of obese adolescents with PCOS and impaired
glucose tolerance is benecial in improving glucose tolerance
and insulin sensitivity, lowering hyperinsulinaemia, and reduc-
ing elevated androgen levels. Metformin therapy was well tol-
erated [12]. Our aim, in this study was to compare the effect of
H.A. El Maghraby et al.
nd/3.0/).
metformin versus combined oral contraceptive pills (COC)
over a 24 month period in adolescent girls with PCOS.
2. Subjects and methods
The study protocol was approved by the Ethics Review Com-
mittee for Human Research in the University of Alexandria,
Egypt.
2.1. Study population
The study included 119 adolescent girls, aged 1520 years, pre-
senting to the outpatient clinic of the Alexandria IVF/ICSI
Centre with hirsutism, acne and menstrual disturbances. PCOS
was dened in these girls by the presence of oligomenorrhoea
(<6 cycles/year) and serum testosterone >1 lg/ml (The Rot-
terdam consensus workshop group, 2004). Suprarenal dysfunc-
tion, hyperprolactinaemia, thyroid dysfunction, or recent
intake of medications likely to affect hormonal prole was a
reason for exclusion from the study. Potential participants
were provided with information about the study and a valid
consent was obtained from those who wished to participate.
None of the patients were taking medications likely to inu-
ence the hormonal prole.
2.2. Protocol of the study
The 119 participants were randomly divided into three groups,
using computer-generated random-number tables: group A
(n = 40) receiving 1700 mg metformin/day, group B (n = 40)
receiving cyclic COC containing 30 lg ethinyl estradiol and
15 mg progestin and group C (n = 39) followed up without
treatment. The study was not blinded (Table 1).
2.3. Assessment and follow up
Initial assessment included body weight, waist-to-hip ratio,
FerrimanGallway score, serum total testosterone level, serum
FSH, LH and prolactin, and transaminases. Insulin resistance
was evaluated using the 75 g oral glucose tolerance test. Sam-
ples were measured 15 min before (fasting sample), and 30, 60,
90, and 120 min after oral consumption of 75 g of glucose and
the glucose/insulin ratio was calculated.
Clinical response, side effects, compliance, serum testoster-
one, fasting and after load insulin and glucose levels were all
assessed at 6 monthly intervals.
Baseline hormonal assays were studied on the day of recruit-
ment for amenorrhoeic patients, while oligomenorrhoeic
patients were studied on day 5 of the menstrual cycle. Follow
up endocrine parameters were measured on day 5 of the rst
menstrual cycle occurring after 5 months of treatment, then
every 6 months, while amenorrhoeic patients were checked on
the planned day of follow up.
Effects of metformin versus combined oral contraceptives in adolescent PCOS
Table 1 Clinical characteristics of the three study groups.
A B
Mean SD
Age (Years) 17.20 2.00
Weight (Kg) 87.00 6.00
Testosterone (lg/ml) 1.50 0.40
Fasting insulin (lIU/L) 18.60 3.00
After-load insulin (lIU/L) 126.00 34.00
GIR 4.10 0.30
Primary outcome measure was improvement in cycle
rhythm and hirsutism. Secondary outcome measures included
weight loss, reduction in serum testosterone levels, and
improvement in fasting and after load serum insulin levels,
and glucose/insulin ratio.
2.4. Hormonal assays
Insulin assay was performed using a solid phase enzyme ampli-
ed sensitivity immunoassay, performed on a microtitre plate
(Medgenix-Ins-EASIA Biosource, Belgium). Performance
characteristics include a minimum detectable concentration
estimated to be 0.15 lIU/ml, intra-assay coefcient of varia-
tion (CV) was 5.33.0%, and inter-assay CV was 5.69.8%
for low and high concentrations, respectively. A direct solid
phase enzyme immunoassay (Bio Chem Immunosystems,
Bologna, Italy) was used for testosterone assay. For serum tes-
tosterone concentrations ranging from 1 to 10 ng/ml, the intra-
and inter-assay CV are 49%, while the lower limit of detec-
tion is approximately 0.1 ng/ml (Conversion factor: 1 ng/
ml = 3.467 nmol/L).
2.5. Statistical analysis
Assuming that the difference in the glucose/insulin ratio (GIR)
between the metformin and oral contraceptive groups would
be 1.0 with a standard deviation of 1.4, the sample size of each
of the study groups was calculated. Based on 0.8 power to
detect a signicant difference (P = 0.05, two-sided), 32
patients were required for each study group. To compensate
for a 20% attrition rate, we planned to enroll 40 patients per
group. Results are reported as mean values SD, unless
otherwise indicated. Statistical analysis of data was done on
an intention-to-treat basis, using SPSS for windows package
release 10.0; SPSS INC. Chicago, IL, USA.
3. Results
Of the 119 participants recruited to the study, there were 29
drop-outs. Eight of these were in the metformin group: three
due to side effects of the drug after 6 months, one due to side
effects after 12 months, one due to non-satisfaction with
results after 18 months, two were non-compliant with taking
the drug regularly despite no side effects, and one was lost to
follow up after 18 months. Seven patients dropped out in the
oral contraceptive group: 4 for weight gain after 12 and
18 months, 2 for side effects after 18 and 24 months, and one
for non compliance without side effects. The control group
133
C
Mean SD Mean SD
16.90 1.60 17.00 2.10
91.00 3.00 84.00 6.00
1.30 0.50 1.20 0.40
15.00 3.00 15.00 2.00
103.00 19.00 100.00 21.00
4.40 0.20 3.90 0.50
had 14 drop-outs: 7 of these due to worsening symptoms
(mainly hirsutism, cycle irregularity and weight gain) after
12 months, and 7 failed to show up after 18 and 24 months
(Fig. 1).
Metformin and COC are associated with a signicant
improvement in cycle regularity (36/40 and 40/40, i.e., 92.5%
and 100%) and subjective improvement of hirsutism (10/40
and 16/40, i.e., 25% and 40%) compared to the control group
(0/40 for both parameters). In the group receiving metformin
(group A), mean serum testosterone dropped signicantly
from 1.5 0.4 to 0.8 0.1 lg/ml by 6 months of treatment.
However by the end of the follow up period, mean serum tes-
tosterone was 1.2 0.3 lg/ml, which is not signicantly differ-
ent from the initial values. In the group receiving COC (group
B) the statistically signicant decline in serum testosterone was
maintained and reached the lowest value by the end of the
2 year duration of the study (0.7 0.2 lg/ml versus
1.3 0.5 lg/ml). In group C, a statistically non-signicant
increase in mean serum testosterone occurred from
1.2 0.4 lg/ml to 1.5 0.4 lg/ml.
Fasting and after-load insulin showed a signicant decline
in group A from a mean of 18.3 3 lIU/L and
126 43 lIU/L to 10 3 lIU/L and 64 15 lIU/L, respec-
tively. A signicant improvement in insulin sensitivity mea-
sured as an increase in glucose/insulin ratio (GIR) occurred
in the same group from 4.1 0.3 lIU/L to 4.6 0.5 lIU/L.
In group B; fasting and after-load insulin increased from
15 3 lIU/L and 103 91 lIU/L to 19 4 lIU/L and
187 22 lIU/L, respectively. GIR decreased signicantly
from 4.4 0.2 to 3.1 0.3 denoting deteriorating insulin sen-
sitivity. In the control group (group C) fasting insulin
increased from 15 2 to 22 3, after load insulin increased
non-signicantly from 100 21 to 111 12 and GIR
decreased from 3.9 0.5 to 3.1 0.3 denoting increasing
insulin resistance.
There was a signicant decline in body weight in group A
from 87 6 to 72 0.5, a non-signicant gain in group C
(from 84 9 to 91 3) and a non-signicant weight gain in
group C (from 84 6 to 91 9 kg), while showed a non sig-
nicant decline in group B (Table 2, Fig. 2).
4. Discussion
The early onset and long natural history of PCOS, together
with the grave long-term consequences of the syndrome as well
as of the medications used, dictate the conduction of interme-
diate and long-term clinical trials before committing these
women to life-long therapeutic lines.
134 H.A. El Maghraby et al.

randomized (n=119)

Metformin group OCP group Control group

(n=40) (n=40) (n=39)

3 DOs (side effects) 4 DOs (worsening

1 DO (non-compliant) symptoms asked
for treatment)

Metformin group OCP group Control group

6m (n=37) (n=39) (n=35)

3 DOs (2 worsening
1 DO (side effects) symptoms, 1asked for
3 DOs (weight gain) treatment)

Metformin group OCP group Control group

12 m (n=36) (n=36) (n=32)

3 DOs (2 non-compliant, 1 3 DOs (lost for follow

2 DOs (1 side effects, 1
up)
not satisfied with drug) weight gain)

Metformin group OCP group Control group

18 m (n=33) (n=34) (n=29)

1 DO (lost for follow up) 1 DO (side effects) 4 DOs (lost for follow
up)

Analysed Analysed Analysed

24 m (n=32) (n=33) (n=25)

NB: DO = Drop outs.

Figure 1 Randomization and retention of patients from recruitment to completion of treatment after 24 weeks in the three study groups.

Table 2 Follow up parameters for the 3 study groups.

Groups Baseline 6 months 12 months 18 months 24 months
Mean SD Mean SD Mean SD Mean SD Mean SD
Testosterone (lg/ml) A 1.50 0.40 0.80 0.10 1.10 0.40 1.30 0.30 1.20 0.30
B 1.30* 0.50 1.00 0.30 0.90 0.40 0.60 0.30 0.70* 0.20
C 1.20 0.40 1.30 0.20 1.00 0.20 1.60 0.20 1.50 0.40
Fasting insulin (lIU/L) A 18.60* 3.00 15.00 4.00 14.00 2.00 9.00 2.00 10.00* 3.00
B 15.00 3.00 14.00 2.00 16.00 4.00 21.00 3.00 19.00 4.00
C 15.00 2.00 13.00 3.00 21.00 5.00 20.00 4.00 22.00 3.00
After-load insulin (lIU/L) A 126.00* 34.00 100.00 31.00 91.00 21.00 82.00 16.00 64.00* 15.00
B 103.00 19.00 100.00 21.00 135.00 41.00 167.00 34.00 187.00 22.00
C 100.00 21.00 110.00 21.00 133.00 29.00 103.00 37.00 111.00 12.00
GIR A 4.10* 0.30 4.00 0.30 3.90 0.30 4.80 0.40 4.60* 0.50
B 4.40* 0.20 4.20 0.30 3.60 0.40 3.60 0.30 3.10* 0.30
C 3.90 0.50 3.90 0.30 4.00 0.30 3.50 0.20 3.10 0.30
Weight (kg) A 87.00* 6.00 82.00 8.00 83.00 5.00 79.00 6.00 72.00* 5.00
B 84.00 9.00 87.00 8.00 90.00 9.00 91.00 10.00 91.00 3.00
C 84.00 6.00 91.00 5.00 97.00 8.00 93.00 7.00 99.00 9.00
*
P value <0.05.

To our knowledge, this study is the rst to follow up ado-
lescent PCOS women for a period of 2 years. The progressive
nature of the metabolic component of the syndrome is clearly
demonstrated by a statistically signicant deterioration of
insulin sensitivity and body weight as demonstrated in the
control group. There is consistent evidence in the literature
that the metabolic syndrome is associated, later in life, with
a high risk of developing type 2 diabetes mellitus, cardiovas-
cular disease and mortality rate [1315]. Taking necessary
measures, at such an early phase of the disease, can have pro-
found benets on the quality of life of these women, as well
as on the general economic burden of the healthcare services
[16].
The hyperandrogenic component of the syndrome, how-
ever, showed an almost stationary course in the control group,
with a very mild rise at the end of 2 years of follow up. The
effect of metformin on hyperandrogenaemia has been reported
in many studies, all of which with a maximum follow up dura-
tion of 12 months [9,17,18]. On following up this effect, we
demonstrate the possible transient nature of this benecial
effect, with an escape of the serum androgen after an initial
improvement of 6 month duration of treatment. Interestingly,
serum androgen levels at the end of 2 years were comparable to
the control group, albeit only slightly lower.
The role of hyperinsulinaemia and abdominal obesity in main-
taining hyperandrogenaemia in PCOS has been demonstrated in
Effects of metformin versus combined oral contraceptives in adolescent PCOS 135

Group A (Metformin)
Group B (Pills) B: Glucose Insulin ratio
A: Serum Testosterone Follow up 5.00
Group C (Control)

1.80
4.50
1.60
Serum Testosterone (ug/ml)

1.40 4.00
1.20

GIR
1.00
3.50 Initial
0.80 After 24 months
3.00
0.60

0.40 2.50
0.20
2.00
0.00
initial 6 months 12 months 18 months 24 months
A B C
Duration of Treatment Study Groups

D: Weight Change C: Mean After-load serum Insulin

105.00 250.00
100.00
95.00 200.00

Serum Insulin (uIU/L)

90.00
150.00
85.00 Initial
Kg

Initial
80.00 After 24 months
After 24 months 100.00
75.00

70.00 50.00
65.00
60.00 0.00
A B C
A B C
Study Groups
Study Groups

Figure 2 Follow up parameters for the three study groups: (A) mean serum testosterone across 6, 12, 18 and 24 months, (B) mean
glucose/insulin ratio (GIR), (C) mean body weight, and (D) mean after-load insulin levels.

many studies, with some attempts at characterizing the complex Oral contraceptive pills have been a traditional long-term
interaction between androgens, insulin, and visceral obesity in therapy for PCOS, to regulate menstrual cycle, protect the
PCOS [1924]. The natural histories of the metabolic syndrome endometrium, and improve hirsutism and acne by reducing
and hyperandrogenaemia, although inter-related at possibly mul- ovarian androgen production [11,34]. These proven advanta-
tiple levels, may not be strictly interdependent; with hyperandro- ges, however, may be counterbalanced by the obvious deterio-
genaemia showing a pre-pubertal rise, a steady course, even ration in insulin-resistance and body weight compared to the
through pregnancy, and a pre-menopausal resolution [7]. The control group, as observed on follow up in our study. In addi-
maintained hyperandrogenaemia, in the metformin group, tion to the potentially grave consequences associated with the
despite signicant weight loss and lower serum insulin levels, pos- acceleration of the metabolic component of PCOS, weight gain
sibly indicates a more fundamental and stable driving mechanism proves to be a particularly challenging side effect in the adoles-
for excessive androgen secretion, with hyperinsulinaemia as a cent age group, effectively undermining patient compliance in
mere exacerbating factor. the long term [21,35,11]. These facts, coupled with the recent
Unlike its effect on hyperandrogenaemia, the benecial evidence of the detrimental effects of oral contraceptives on
effect of metformin on the metabolic syndrome [25], of which the low-grade inammatory state suspected to mediate athero-
insulin resistance and body weight were taken as indices, con- sclerosis in PCOS patients [36], should warrant a degree of
tinues to improve throughout the 2 year-follow up period of caution in prescribing oral contraceptives for these adoles-
this study. In this context, initiation of insulin sensitizer ther- cents, on a long-term basis. If the main complaints are limited
apy at such an early age appears to be an appropriate preven- to acne and hirsutism, insulin-sensitizers are obviously advan-
tive measure [26]. However, the added advantage of correcting tageous, but if the main aim is menstrual cycle control, oral
serum androgens, suggested by some trials, may be debatable contraceptives have clear advantages in terms of effectiveness
[2729]. This goal may be achieved by the adjunctive use of and cost. Their use with proper monitoring risk factors, or
an antiandrogen which, although effective, needs to be justied in conjunction with other modalities of therapy, including
in the long-term, as the existence of a correlation between hypo-caloric restriction, exercise [23], insulin-sensitizers, and/
hyperandrogenaemia per se and late cardiovascular complica- or an antiandrogen [21,3133] may limit the risk of serious
tions in PCOS women is, so far, contradictory [6,30]. Further- long-term complications [37,21,38,39,3133].
more, as conrmed in our study, insulin sensitizers alone seem The choice of the proper line of therapy should be tailored
to provide a level of patient satisfaction as regards hirsutism, for every patient, according to her age, stage in life, presenting
which is comparable to oral contraceptives [11]. However, symptoms, various personal and familial risk indices, as well as
adjunctive anti-androgens may have a role in improving the her own informed choices. This study suggests that insulin sen-
results of fertility therapy [21,3133]. sitizers are a proper choice for adolescent PCOS women pre-
136
senting with acne and hirsutism, having a safer prole than
combined oral contraceptives.
5. Capsule
Metformin and COC have comparable therapeutic effective-
ness on cycle regularity and hirsutism. Metformin was associ-
ated with signicant weight loss and improvement in the
metabolic syndrome, while COC was associated with non-sig-
nicant weight gain and deterioration of the metabolic
syndrome.
Conict of interest
We have no conict of interest to declare.
References
[1] Hassan A, Gordon CM. Polycystic ovary syndrome update in
adolescence. Curr. Opin. Pediatr. 2007;19:38997.
[2] Coviello AD, Legro RS, Dunaif A. Adolescent girls with
polycystic ovary syndrome have an increased risk of the metabolic
syndrome associated with increasing androgen levels independent
of obesity and insulin resistance. J. Clin. Endocrinol. Metab.
2006;91:4927.
[3] Hollinrake E, Abreu A, Maifeld M, Van Voorhis BJ, Dokras A.
Increased risk of depressive disorders in women with polycystic
ovary syndrome. Fertil. Steril. 2007;87:136976.
[4] Trent ME, Rich M, Austin SB, Gordon CM. Quality of life in
adolescent girls with polycystic ovary syndrome. Arch. Pediatr.
Adolesc. Med. 2002;156:55660.
[5] Xita N, Papassotiriou I, Georgiou I, Vounatsou M, Margeli A,
Tsatsoulis A. The adiponectin-to-leptin ratio in women with
polycystic ovary syndrome: relation to insulin resistance and
proinammatory markers. Metabolism 2007;56:76671.
[6] Shroff R, Syrop CH, Davis W, Van Voorhis BJ, Dokras A. Risk
of metabolic complications in the new PCOS phenotypes based on
the Rotterdam criteria. Fertil. Steril. 2007;88:138995.
[7] Pasquali R, Gambineri A. Polycystic ovary syndrome: a multi-
faceted disease from adolescence to adult age. Ann. N.Y. Acad.
Sci. 2006;1092:15874.
[8] Pasquali R, Patton L, Pagotto U, Gambineri A. Metabolic
alterations and cardiovascular risk factors in the polycystic ovary
syndrome. Minerva Ginecol. 2005;57:7985.
[9] Allen HF, Mazzoni C, Heptulla RA, Murray MA, Miller N,
Koenigs L, et al. Randomized controlled trial evaluating response
to metformin versus standard therapy in the treatment of
adolescents with polycystic ovary syndrome. J. Pediatr. Endocri-
nol. Metab. 2005;18:7618.
[10] Costello M, Shrestha B, Eden J, Sjoblom P, Johnson N. Insulin-
sensitising drugs versus the combined oral contraceptive pill for
hirsutism, acne and risk of diabetes, cardiovascular disease, and
endometrial cancer in polycystic ovary syndrome. Cochrane
Database Syst. Rev. 2007:CD005552.
[11] Costello MF, Shrestha B, Eden J, Johnson NP, Sjoblom P.
Metformin versus oral contraceptive pill in polycystic ovary
syndrome: a Cochrane review. Hum. Reprod. 2007;22:12009.
[12] Arslanian SA, Lewy V, Danadian K, Saad R. Metformin therapy
in obese adolescents with polycystic ovary syndrome and impaired
glucose tolerance: amelioration of exaggerated adrenal response
to adrenocorticotropin with reduction of insulinemia/insulin
resistance. J. Clin. Endocrinol. Metab. 2002;87:15559.
[13] Dokras A. Cardiovascular disease risk factors in polycystic ovary
syndrome. Semin. Reprod. Med. 2008;26:3944.
H.A. El Maghraby et al.
[14] Shroff R, Kerchner A, Maifeld M, Van Beek EJ, Jagasia D,
Dokras A. Young obese women with polycystic ovary syndrome
have evidence of early coronary atherosclerosis. J. Clin. Endocri-
nol. Metab. 2007;92:460914.
[15] Essah PA, Wickham EP, Nestler JE. The metabolic syndrome in
polycystic ovary syndrome. Clin. Obstet. Gynecol.
2007;50:20525.
[16] Azziz R, Marin C, Hoq L, Badamgarav E, Song P. Health care-
related economic burden of the polycystic ovary syndrome during
the reproductive life span. J. Clin. Endocrinol. Metab.
2005;90:46508.
[17] Harwood K, Vuguin P, Martino-Nardi J. Current approaches to
the diagnosis and treatment of polycystic ovarian syndrome in
youth. Horm. Res. 2007;68:20917.
[18] Ortega-Gonzalez C, Luna S, Hernandez L, Crespo G, Aguayo P,
rteaga-Troncoso G, et al. Responses of serum androgen and
insulin resistance to metformin and pioglitazone in obese, insulin-
resistant women with polycystic ovary syndrome. J. Clin. Endo-
crinol. Metab. 2005;90:13605.
[19] Quinkler M, Sinha B, Tomlinson JW, Bujalska IJ, Stewart PM,
Arlt W. Androgen generation in adipose tissue in women with
simple obesitya site-specic role for 17beta-hydroxysteroid
dehydrogenase type 5. J. Endocrinol. 2004;183:33142.
[20] Guido M, Romualdi D, De ML, Porcelli T, Giuliani M,
Costantini B, et al. Administration of exogenous ghrelin in obese
patients with polycystic ovary syndrome: effects on plasma levels
of growth hormone, glucose, and insulin. Fertil. Steril.
2007;88:12530.
[21] Hahn S, Benson S, Elsenbruch S, Pleger K, Tan S, Mann K, et al.
Metformin treatment of polycystic ovary syndrome improves
health-related quality-of-life, emotional distress and sexuality.
Hum. Reprod. 2006;21:192534.
[22] Blank SK, McCartney CR, Helm KD, Marshall JC. Neuroendo-
crine effects of androgens in adult polycystic ovary syndrome and
female puberty. Semin. Reprod. Med. 2007;25:3529.
[23] Pasquali R, Gambineri A, Pagotto U. The impact of obesity on
reproduction in women with polycystic ovary syndrome. BJOG
2006;113:114859.
[24] Blank SK, McCartney CR, Marshall JC. The origins and sequelae
of abnormal neuroendocrine function in polycystic ovary syn-
drome. Hum. Reprod. Update 2006;12:35161.
[25] Pasquali R, Gambineri A. Insulin-sensitizing agents in women
with polycystic ovary syndrome. Fertil. Steril. 2006;86(Suppl.
):S289.
[26] Nestler JE. Metformin for the treatment of the polycystic ovary
syndrome. N. Engl. J. Med. 2008;358:4754.
[27] Genazzani AD, Lanzoni C, Ricchieri F, Baraldi E, Casarosa E,
Jasonni VM. Metformin administration is more effective when
non-obese patients with polycystic ovary syndrome show both
hyperandrogenism and hyperinsulinemia. Gynecol. Endocrinol.
2007;23:14652.
[28] De LV, Musacchio MC, Morgante G, Piomboni P, Petraglia F.
Metformin treatment is effective in obese teenage girls with PCOS.
Hum. Reprod. 2006;21:22526.
[29] Balen AH, Rutherford AJ. Managing anovulatory infertility and
polycystic ovary syndrome. BMJ 2007;335:6636.
[30] Dokras A, Jagasia DH, Maifeld M, Sinkey CA, VanVoorhis BJ,
Haynes WG. Obesity and insulin resistance but not hyperandrog-
enism mediates vascular dysfunction in women with polycystic
ovary syndrome. Fertil. Steril. 2006;86:17029.
[31] Ibanez L, de ZF. Low-dose combination of utamide, metformin
and an oral contraceptive for non-obese, young women with
polycystic ovary syndrome. Hum. Reprod. 2003;18:5760.
[32] Ibanez L, Ong K, Ferrer A, Amin R, Dunger D, de ZF. Low-dose
utamide-metformin therapy reverses insulin resistance and
reduces fat mass in nonobese adolescents with ovarian hyperan-
drogenism. J. Clin. Endocrinol. Metab. 2003;88:26006.
Effects of metformin versus combined oral contraceptives in adolescent PCOS 137

[33] Ibanez L, de ZF. Low-dose utamide-metformin therapy for aggravation by oral contraception. Hum. Reprod.
hyperinsulinemic hyperandrogenism in non-obese adolescents and 2005;20:245762.
women. Hum. Reprod. Update 2006;12:24352. [37] Orio F, Manguso F, Di BS, Falbo A, Giallauria F, Labella D,
[34] Hillard PJ. Oral contraceptives and the management of hyperan- et al. Metformin administration improves leukocyte count in
drogenism-polycystic ovary syndrome in adolescents. Endocrinol. women with polycystic ovary syndrome: a 6-month prospective
Metab. Clin. North Am. 2005;34:70723. study. Eur. J. Endocrinol. 2007;157:6973.
[35] Welt CK, Gudmundsson JA, Arason G, Adams J, Palsdottir H, [38] Hart R, Norman R. Polycystic ovarian syndromeprognosis and
Gudlaugsdottir G, et al. Characterizing discrete subsets of outcomes. Best Pract. Res. Clin. Obstet. Gynaecol.
polycystic ovary syndrome as dened by the Rotterdam criteria: 2006;20:75178.
the impact of weight on phenotype and metabolic features. J. Clin. [39] Warren-Ulanch J, Arslanian S. Treatment of PCOS in adoles-
Endocrinol. Metab. 2006;91:48428. cence. Best Pract. Res. Clin. Endocrinol. Metab. 2006;20:31130.
[36] Ibanez L, Jaramillo AM, Ferrer A, de ZF. High neutrophil count
in girls and women with hyperinsulinaemic hyperandrogenism:
normalization with metformin and utamide overcomes the