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Randomized controlled trial of the effects of metformin versus combined oral contraceptives in adolescent PCOS women through a 24 month follow up period
Middle East Fertility Society Journal (2015) 20, 131–137
Middle East Fertility Society
Middle East Fertility Society Journal www.mefsjournal.org www.sciencedirect.com
ORIGINAL ARTICLE
Randomized controlled trial of the effects of metformin versus combined oral contraceptives in adolescent PCOS women through a 24 month follow up period H.A. El Maghraby
a,d
, T. Nafee
a,c
, D. Guiziry
b,d
, A. Elnashar
e,*
a
Department of Obstetrics and Gynecology, Faculty of Medicine, University of Alexandria, Egypt 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 b
Received 18 October 2014; accepted 19 October 2014 Available online 27 November 2014
KEYWORDS Adolescent; Polycystic ovary; Insulin resistance; Metformin; Combined oral contraceptive
Abstract Objective: To compare metformin and combined oral contraceptive pill (COC) effects over 24 months in adolescent PCOS. Design: Randomized controlled study. Setting: Alexandria ICSI centre. Patients: 117 adolescent girls with PCOS, were randomized to: group A (n = 40): metformin, group B (n = 40): COC, and group C (n = 39): control. Interventions: Group A: received metformin, group B: received combined oral contraceptives. Main outcome measures: Improvement in cycle rhythm and hirsutism. Results: In group B a significant 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 significant decline in fasting (18.6 ± 3.0– 10.0 ± 3.0 lIU/ml) and after-load insulin levels (126 ± 43–64 ± 15 lIU/ml) with a significant rise in glucose/insulin ratio (GIR) from 4.1 ± 0.3 to 4.6 ± 0.5. Group B showed a significant 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 significantly from 4.4 ± 0.2 to 3.1 ± 0.3. Metformin was associated with a significant loss of weight from 87.0 ± 6.0 to 72.0 ± 0.5 kg while COC was associated with a non-significant 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 significant improvement in met-
* Corresponding author at: Faculty of Medicine, University of Benha, 24 Gomhoria St., Mansura, Egypt. Tel.: +20 1066934749. E-mail address: [email protected] (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 Ó 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/).
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H.A. El Maghraby et al. abolic syndrome, while COC was associated with a deterioration of metabolic syndrome. Ó 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-ncnd/3.0/).
1. Introduction Adolescent polycystic ovary syndrome (PCOS) represents a distinct clinical variant of a notoriously heterogeneous disorder. The condition affects a substantial number of adolescent girls with reportedly increasing incidence, probably in association 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 syndrome [2]; hence, the importance of correcting the underlying metabolic derangement in these young women. The newly recognized association between PCOS, particularly adolescent form, and depressive disorders [3], lower health-related quality of life (HRQL) [4] and systemic low grade inflammation [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 prophylactic; aiming at restoration of body weight, cycle regulation, reducing signs of hyperandrogenism, and prevention of longterm health hazards. Treatment of this particular group of young patients should consider safety, acceptability, compliance, 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 syndrome, 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 similar beneficial 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 randomized 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 clinical 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-disciplinary debate. A non-randomized study showed that metformin treatment of obese adolescents with PCOS and impaired glucose tolerance is beneficial in improving glucose tolerance and insulin sensitivity, lowering hyperinsulinaemia, and reducing elevated androgen levels. Metformin therapy was well tolerated [12]. Our aim, in this study was to compare the effect of
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 Committee for Human Research in the University of Alexandria, Egypt. 2.1. Study population The study included 119 adolescent girls, aged 15–20 years, presenting to the outpatient clinic of the Alexandria IVF/ICSI Centre with hirsutism, acne and menstrual disturbances. PCOS was defined in these girls by the presence of oligomenorrhoea (<6 cycles/year) and serum testosterone >1 lg/ml (The Rotterdam consensus workshop group, 2004). Suprarenal dysfunction, hyperprolactinaemia, thyroid dysfunction, or recent intake of medications likely to affect hormonal profile 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 influence the hormonal profile. 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, Ferriman–Gallway score, serum total testosterone level, serum FSH, LH and prolactin, and transaminases. Insulin resistance was evaluated using the 75 g oral glucose tolerance test. Samples 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 testosterone, fasting and after load insulin and glucose levels were all assessed at 6 monthly intervals. Baseline hormonal assays were studied on the day of recruitment 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 first 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
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Clinical characteristics of the three study groups. A
Age (Years) Weight (Kg) Testosterone (lg/ml) Fasting insulin (lIU/L) After-load insulin (lIU/L) GIR
B
C
Mean
SD
Mean
SD
Mean
SD
17.20 87.00 1.50 18.60 126.00 4.10
2.00 6.00 0.40 3.00 34.00 0.30
16.90 91.00 1.30 15.00 103.00 4.40
1.60 3.00 0.50 3.00 19.00 0.20
17.00 84.00 1.20 15.00 100.00 3.90
2.10 6.00 0.40 2.00 21.00 0.50
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 amplified 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 coefficient of variation (CV) was 5.3–3.0%, and inter-assay CV was 5.6–9.8% for low and high concentrations, respectively. A direct solid phase enzyme immunoassay (Bio Chem Immunosystems, Bologna, Italy) was used for testosterone assay. For serum testosterone concentrations ranging from 1 to 10 ng/ml, the intraand inter-assay CV are 4–9%, while the lower limit of detection 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 significant 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
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 significant 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 significantly 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 testosterone was 1.2 ± 0.3 lg/ml, which is not significantly different from the initial values. In the group receiving COC (group B) the statistically significant 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-significant 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 significant 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, respectively. A significant improvement in insulin sensitivity measured 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 significantly from 4.4 ± 0.2 to 3.1 ± 0.3 denoting deteriorating insulin sensitivity. In the control group (group C) fasting insulin increased from 15 ± 2 to 22 ± 3, after load insulin increased non-significantly 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 significant decline in body weight in group A from 87 ± 6 to 72 ± 0.5, a non-significant gain in group C (from 84 ± 9 to 91 ± 3) and a non-significant weight gain in group C (from 84 ± 6 to 91 ± 9 kg), while showed a non significant 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 intermediate and long-term clinical trials before committing these women to life-long therapeutic lines.
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H.A. El Maghraby et al.
randomized (n=119)
Metformin group (n=40)
OCP group (n=40)
3 DOs (side effects)
6m
Control group (n=39) 4 DOs (worsening symptoms asked for treatment)
1 DO (non-compliant)
Metformin group (n=37)
OCP group (n=39)
Control group (n=35) 3 DOs (2 worsening symptoms, 1asked for treatment)
1 DO (side effects) 3 DOs (weight gain)
12 m
Metformin group (n=36)
OCP group (n=36)
3 DOs (2 non-compliant, 1 not satisfied with drug)
18 m
Metformin group (n=33)
3 DOs (lost for follow up)
2 DOs (1 side effects, 1 weight gain) OCP group (n=34)
Control group (n=29)
1 DO (side effects)
1 DO (lost for follow up) Analysed (n=32)
24 m
Control group (n=32)
4 DOs (lost for follow up)
Analysed (n=33)
Analysed (n=25)
NB: ‘DO’ = Drop outs.
Figure 1
Table 2
Randomization and retention of patients from recruitment to completion of treatment after 24 weeks in the three study groups.
Follow up parameters for the 3 study groups. Groups
Testosterone (lg/ml)
Fasting insulin (lIU/L)
After-load insulin (lIU/L)
GIR
Weight (kg)
*
A B C A B C A B C A B C A B C
Baseline
6 months
12 months
18 months
24 months
Mean
SD
Mean
SD
Mean
SD
Mean
SD
Mean
SD
1.50 1.30* 1.20 18.60* 15.00 15.00 126.00* 103.00 100.00 4.10* 4.40* 3.90 87.00* 84.00 84.00
0.40 0.50 0.40 3.00 3.00 2.00 34.00 19.00 21.00 0.30 0.20 0.50 6.00 9.00 6.00
0.80 1.00 1.30 15.00 14.00 13.00 100.00 100.00 110.00 4.00 4.20 3.90 82.00 87.00 91.00
0.10 0.30 0.20 4.00 2.00 3.00 31.00 21.00 21.00 0.30 0.30 0.30 8.00 8.00 5.00
1.10 0.90 1.00 14.00 16.00 21.00 91.00 135.00 133.00 3.90 3.60 4.00 83.00 90.00 97.00
0.40 0.40 0.20 2.00 4.00 5.00 21.00 41.00 29.00 0.30 0.40 0.30 5.00 9.00 8.00
1.30 0.60 1.60 9.00 21.00 20.00 82.00 167.00 103.00 4.80 3.60 3.50 79.00 91.00 93.00
0.30 0.30 0.20 2.00 3.00 4.00 16.00 34.00 37.00 0.40 0.30 0.20 6.00 10.00 7.00
1.20 0.70* 1.50 10.00* 19.00 22.00 64.00* 187.00 111.00 4.60* 3.10* 3.10 72.00* 91.00 99.00
0.30 0.20 0.40 3.00 4.00 3.00 15.00 22.00 12.00 0.50 0.30 0.30 5.00 3.00 9.00
P value <0.05.
To our knowledge, this study is the first to follow up adolescent PCOS women for a period of 2 years. The progressive nature of the metabolic component of the syndrome is clearly demonstrated by a statistically significant 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, cardiovascular disease and mortality rate [13–15]. Taking necessary measures, at such an early phase of the disease, can have profound benefits 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, however, 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 duration of 12 months [9,17,18]. On following up this effect, we demonstrate the possible transient nature of this beneficial 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 maintaining hyperandrogenaemia in PCOS has been demonstrated in
Effects of metformin versus combined oral contraceptives in adolescent PCOS
135
Group A (Metformin)
A: Serum Testosterone Follow up
B: Glucose Insulin ratio
Group B (Pills)
5.00
Group C (Control)
1.80
4.50
1.40
4.00
1.20
GIR
Serum Testosterone (ug/ml)
1.60
1.00 0.80
3.50
Initial
3.00
After 24 months
0.60
2.50
0.40 0.20
2.00
0.00 initial
6 months
12 months
18 months
A
24 months
B
C
Study Groups
Duration of Treatment
C: Mean After-load serum Insulin
D: Weight Change 105.00
250.00
95.00
Kg
90.00 85.00 Initial
80.00
After 24 months
75.00 70.00
Serum Insulin (uIU/L)
100.00 200.00
150.00
Initial After 24 months
100.00
50.00
65.00 0.00
60.00 A
B
C
Study Groups
A
B
C
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 interaction between androgens, insulin, and visceral obesity in PCOS [19–24]. The natural histories of the metabolic syndrome and hyperandrogenaemia, although inter-related at possibly multiple levels, may not be strictly interdependent; with hyperandrogenaemia showing a pre-pubertal rise, a steady course, even through pregnancy, and a pre-menopausal resolution [7]. The maintained hyperandrogenaemia, in the metformin group, despite significant weight loss and lower serum insulin levels, possibly indicates a more fundamental and stable driving mechanism for excessive androgen secretion, with hyperinsulinaemia as a mere exacerbating factor. Unlike its effect on hyperandrogenaemia, the beneficial effect of metformin on the metabolic syndrome [25], of which insulin resistance and body weight were taken as indices, continues to improve throughout the 2 year-follow up period of this study. In this context, initiation of insulin sensitizer therapy at such an early age appears to be an appropriate preventive measure [26]. However, the added advantage of correcting serum androgens, suggested by some trials, may be debatable [27–29]. This goal may be achieved by the adjunctive use of an antiandrogen which, although effective, needs to be justified in the long-term, as the existence of a correlation between hyperandrogenaemia per se and late cardiovascular complications in PCOS women is, so far, contradictory [6,30]. Furthermore, as confirmed in our study, insulin sensitizers alone seem to provide a level of patient satisfaction as regards hirsutism, which is comparable to oral contraceptives [11]. However, adjunctive anti-androgens may have a role in improving the results of fertility therapy [21,31–33].
Oral contraceptive pills have been a traditional long-term therapy for PCOS, to regulate menstrual cycle, protect the endometrium, and improve hirsutism and acne by reducing ovarian androgen production [11,34]. These proven advantages, however, may be counterbalanced by the obvious deterioration in insulin-resistance and body weight compared to the control group, as observed on follow up in our study. In addition to the potentially grave consequences associated with the acceleration of the metabolic component of PCOS, weight gain proves to be a particularly challenging side effect in the adolescent age group, effectively undermining patient compliance in the long term [21,35,11]. These facts, coupled with the recent evidence of the detrimental effects of oral contraceptives on the low-grade inflammatory state suspected to mediate atherosclerosis in PCOS patients [36], should warrant a degree of caution in prescribing oral contraceptives for these adolescents, on a long-term basis. If the main complaints are limited to acne and hirsutism, insulin-sensitizers are obviously advantageous, but if the main aim is menstrual cycle control, oral contraceptives have clear advantages in terms of effectiveness and cost. Their use with proper monitoring risk factors, or in conjunction with other modalities of therapy, including hypo-caloric restriction, exercise [23], insulin-sensitizers, and/ or an antiandrogen [21,31–33] may limit the risk of serious long-term complications [37,21,38,39,31–33]. The choice of the proper line of therapy should be tailored for every patient, according to her age, stage in life, presenting symptoms, various personal and familial risk indices, as well as her own informed choices. This study suggests that insulin sensitizers are a proper choice for adolescent PCOS women pre-
136 senting with acne and hirsutism, having a safer profile than combined oral contraceptives. 5. Capsule Metformin and COC have comparable therapeutic effectiveness on cycle regularity and hirsutism. Metformin was associated with significant weight loss and improvement in the metabolic syndrome, while COC was associated with non-significant weight gain and deterioration of the metabolic syndrome. Conflict of interest We have no conflict of interest to declare. References [1] Hassan A, Gordon CM. Polycystic ovary syndrome update in adolescence. Curr. Opin. Pediatr. 2007;19:389–97. [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;91:492–7. [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;87:1369–76. [4] Trent ME, Rich M, Austin SB, Gordon CM. Quality of life in adolescent girls with polycystic ovary syndrome. Arch. Pediatr. Adolesc. Med. 2002;156:556–60. [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 proinflammatory markers. Metabolism 2007;56:766–71. [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;88:1389–95. [7] Pasquali R, Gambineri A. Polycystic ovary syndrome: a multifaceted disease from adolescence to adult age. Ann. N.Y. Acad. Sci. 2006;1092:158–74. [8] Pasquali R, Patton L, Pagotto U, Gambineri A. Metabolic alterations and cardiovascular risk factors in the polycystic ovary syndrome. Minerva Ginecol. 2005;57:79–85. [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. Endocrinol. Metab. 2005;18:761–8. [10] Costello M, Shrestha B, Eden J, Sjoblom P, Johnson N. Insulinsensitising 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;22:1200–9. [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;87:1555–9. [13] Dokras A. Cardiovascular disease risk factors in polycystic ovary syndrome. Semin. Reprod. Med. 2008;26:39–44.
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Effects of metformin versus combined oral contraceptives in adolescent PCOS [33] Ibanez L, de ZF. Low-dose flutamide-metformin therapy for hyperinsulinemic hyperandrogenism in non-obese adolescents and women. Hum. Reprod. Update 2006;12:243–52. [34] Hillard PJ. Oral contraceptives and the management of hyperandrogenism-polycystic ovary syndrome in adolescents. Endocrinol. Metab. Clin. North Am. 2005;34:707–23. [35] Welt CK, Gudmundsson JA, Arason G, Adams J, Palsdottir H, Gudlaugsdottir G, et al. Characterizing discrete subsets of polycystic ovary syndrome as defined by the Rotterdam criteria: the impact of weight on phenotype and metabolic features. J. Clin. Endocrinol. Metab. 2006;91:4842–8. [36] Ibanez L, Jaramillo AM, Ferrer A, de ZF. High neutrophil count in girls and women with hyperinsulinaemic hyperandrogenism: normalization with metformin and flutamide overcomes the
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aggravation by oral contraception. Hum. Reprod. 2005;20:2457–62. [37] Orio F, Manguso F, Di BS, Falbo A, Giallauria F, Labella D, et al. Metformin administration improves leukocyte count in women with polycystic ovary syndrome: a 6-month prospective study. Eur. J. Endocrinol. 2007;157:69–73. [38] Hart R, Norman R. Polycystic ovarian syndrome–prognosis and outcomes. Best Pract. Res. Clin. Obstet. Gynaecol. 2006;20:751–78. [39] Warren-Ulanch J, Arslanian S. Treatment of PCOS in adolescence. Best Pract. Res. Clin. Endocrinol. Metab. 2006;20:311–30.
Middle East Fertility Society
Middle East Fertility Society Journal www.mefsjournal.org www.sciencedirect.com
ORIGINAL ARTICLE
Randomized controlled trial of the effects of metformin versus combined oral contraceptives in adolescent PCOS women through a 24 month follow up period H.A. El Maghraby
a,d
, T. Nafee
a,c
, D. Guiziry
b,d
, A. Elnashar
e,*
a
Department of Obstetrics and Gynecology, Faculty of Medicine, University of Alexandria, Egypt 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 b
Received 18 October 2014; accepted 19 October 2014 Available online 27 November 2014
KEYWORDS Adolescent; Polycystic ovary; Insulin resistance; Metformin; Combined oral contraceptive
Abstract Objective: To compare metformin and combined oral contraceptive pill (COC) effects over 24 months in adolescent PCOS. Design: Randomized controlled study. Setting: Alexandria ICSI centre. Patients: 117 adolescent girls with PCOS, were randomized to: group A (n = 40): metformin, group B (n = 40): COC, and group C (n = 39): control. Interventions: Group A: received metformin, group B: received combined oral contraceptives. Main outcome measures: Improvement in cycle rhythm and hirsutism. Results: In group B a significant 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 significant decline in fasting (18.6 ± 3.0– 10.0 ± 3.0 lIU/ml) and after-load insulin levels (126 ± 43–64 ± 15 lIU/ml) with a significant rise in glucose/insulin ratio (GIR) from 4.1 ± 0.3 to 4.6 ± 0.5. Group B showed a significant 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 significantly from 4.4 ± 0.2 to 3.1 ± 0.3. Metformin was associated with a significant loss of weight from 87.0 ± 6.0 to 72.0 ± 0.5 kg while COC was associated with a non-significant 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 significant improvement in met-
* Corresponding author at: Faculty of Medicine, University of Benha, 24 Gomhoria St., Mansura, Egypt. Tel.: +20 1066934749. E-mail address: [email protected] (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 Ó 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/).
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H.A. El Maghraby et al. abolic syndrome, while COC was associated with a deterioration of metabolic syndrome. Ó 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-ncnd/3.0/).
1. Introduction Adolescent polycystic ovary syndrome (PCOS) represents a distinct clinical variant of a notoriously heterogeneous disorder. The condition affects a substantial number of adolescent girls with reportedly increasing incidence, probably in association 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 syndrome [2]; hence, the importance of correcting the underlying metabolic derangement in these young women. The newly recognized association between PCOS, particularly adolescent form, and depressive disorders [3], lower health-related quality of life (HRQL) [4] and systemic low grade inflammation [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 prophylactic; aiming at restoration of body weight, cycle regulation, reducing signs of hyperandrogenism, and prevention of longterm health hazards. Treatment of this particular group of young patients should consider safety, acceptability, compliance, 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 syndrome, 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 similar beneficial 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 randomized 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 clinical 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-disciplinary debate. A non-randomized study showed that metformin treatment of obese adolescents with PCOS and impaired glucose tolerance is beneficial in improving glucose tolerance and insulin sensitivity, lowering hyperinsulinaemia, and reducing elevated androgen levels. Metformin therapy was well tolerated [12]. Our aim, in this study was to compare the effect of
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 Committee for Human Research in the University of Alexandria, Egypt. 2.1. Study population The study included 119 adolescent girls, aged 15–20 years, presenting to the outpatient clinic of the Alexandria IVF/ICSI Centre with hirsutism, acne and menstrual disturbances. PCOS was defined in these girls by the presence of oligomenorrhoea (<6 cycles/year) and serum testosterone >1 lg/ml (The Rotterdam consensus workshop group, 2004). Suprarenal dysfunction, hyperprolactinaemia, thyroid dysfunction, or recent intake of medications likely to affect hormonal profile 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 influence the hormonal profile. 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, Ferriman–Gallway score, serum total testosterone level, serum FSH, LH and prolactin, and transaminases. Insulin resistance was evaluated using the 75 g oral glucose tolerance test. Samples 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 testosterone, fasting and after load insulin and glucose levels were all assessed at 6 monthly intervals. Baseline hormonal assays were studied on the day of recruitment 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 first 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
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Clinical characteristics of the three study groups. A
Age (Years) Weight (Kg) Testosterone (lg/ml) Fasting insulin (lIU/L) After-load insulin (lIU/L) GIR
B
C
Mean
SD
Mean
SD
Mean
SD
17.20 87.00 1.50 18.60 126.00 4.10
2.00 6.00 0.40 3.00 34.00 0.30
16.90 91.00 1.30 15.00 103.00 4.40
1.60 3.00 0.50 3.00 19.00 0.20
17.00 84.00 1.20 15.00 100.00 3.90
2.10 6.00 0.40 2.00 21.00 0.50
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 amplified 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 coefficient of variation (CV) was 5.3–3.0%, and inter-assay CV was 5.6–9.8% for low and high concentrations, respectively. A direct solid phase enzyme immunoassay (Bio Chem Immunosystems, Bologna, Italy) was used for testosterone assay. For serum testosterone concentrations ranging from 1 to 10 ng/ml, the intraand inter-assay CV are 4–9%, while the lower limit of detection 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 significant 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
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 significant 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 significantly 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 testosterone was 1.2 ± 0.3 lg/ml, which is not significantly different from the initial values. In the group receiving COC (group B) the statistically significant 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-significant 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 significant 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, respectively. A significant improvement in insulin sensitivity measured 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 significantly from 4.4 ± 0.2 to 3.1 ± 0.3 denoting deteriorating insulin sensitivity. In the control group (group C) fasting insulin increased from 15 ± 2 to 22 ± 3, after load insulin increased non-significantly 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 significant decline in body weight in group A from 87 ± 6 to 72 ± 0.5, a non-significant gain in group C (from 84 ± 9 to 91 ± 3) and a non-significant weight gain in group C (from 84 ± 6 to 91 ± 9 kg), while showed a non significant 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 intermediate and long-term clinical trials before committing these women to life-long therapeutic lines.
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H.A. El Maghraby et al.
randomized (n=119)
Metformin group (n=40)
OCP group (n=40)
3 DOs (side effects)
6m
Control group (n=39) 4 DOs (worsening symptoms asked for treatment)
1 DO (non-compliant)
Metformin group (n=37)
OCP group (n=39)
Control group (n=35) 3 DOs (2 worsening symptoms, 1asked for treatment)
1 DO (side effects) 3 DOs (weight gain)
12 m
Metformin group (n=36)
OCP group (n=36)
3 DOs (2 non-compliant, 1 not satisfied with drug)
18 m
Metformin group (n=33)
3 DOs (lost for follow up)
2 DOs (1 side effects, 1 weight gain) OCP group (n=34)
Control group (n=29)
1 DO (side effects)
1 DO (lost for follow up) Analysed (n=32)
24 m
Control group (n=32)
4 DOs (lost for follow up)
Analysed (n=33)
Analysed (n=25)
NB: ‘DO’ = Drop outs.
Figure 1
Table 2
Randomization and retention of patients from recruitment to completion of treatment after 24 weeks in the three study groups.
Follow up parameters for the 3 study groups. Groups
Testosterone (lg/ml)
Fasting insulin (lIU/L)
After-load insulin (lIU/L)
GIR
Weight (kg)
*
A B C A B C A B C A B C A B C
Baseline
6 months
12 months
18 months
24 months
Mean
SD
Mean
SD
Mean
SD
Mean
SD
Mean
SD
1.50 1.30* 1.20 18.60* 15.00 15.00 126.00* 103.00 100.00 4.10* 4.40* 3.90 87.00* 84.00 84.00
0.40 0.50 0.40 3.00 3.00 2.00 34.00 19.00 21.00 0.30 0.20 0.50 6.00 9.00 6.00
0.80 1.00 1.30 15.00 14.00 13.00 100.00 100.00 110.00 4.00 4.20 3.90 82.00 87.00 91.00
0.10 0.30 0.20 4.00 2.00 3.00 31.00 21.00 21.00 0.30 0.30 0.30 8.00 8.00 5.00
1.10 0.90 1.00 14.00 16.00 21.00 91.00 135.00 133.00 3.90 3.60 4.00 83.00 90.00 97.00
0.40 0.40 0.20 2.00 4.00 5.00 21.00 41.00 29.00 0.30 0.40 0.30 5.00 9.00 8.00
1.30 0.60 1.60 9.00 21.00 20.00 82.00 167.00 103.00 4.80 3.60 3.50 79.00 91.00 93.00
0.30 0.30 0.20 2.00 3.00 4.00 16.00 34.00 37.00 0.40 0.30 0.20 6.00 10.00 7.00
1.20 0.70* 1.50 10.00* 19.00 22.00 64.00* 187.00 111.00 4.60* 3.10* 3.10 72.00* 91.00 99.00
0.30 0.20 0.40 3.00 4.00 3.00 15.00 22.00 12.00 0.50 0.30 0.30 5.00 3.00 9.00
P value <0.05.
To our knowledge, this study is the first to follow up adolescent PCOS women for a period of 2 years. The progressive nature of the metabolic component of the syndrome is clearly demonstrated by a statistically significant 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, cardiovascular disease and mortality rate [13–15]. Taking necessary measures, at such an early phase of the disease, can have profound benefits 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, however, 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 duration of 12 months [9,17,18]. On following up this effect, we demonstrate the possible transient nature of this beneficial 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 maintaining hyperandrogenaemia in PCOS has been demonstrated in
Effects of metformin versus combined oral contraceptives in adolescent PCOS
135
Group A (Metformin)
A: Serum Testosterone Follow up
B: Glucose Insulin ratio
Group B (Pills)
5.00
Group C (Control)
1.80
4.50
1.40
4.00
1.20
GIR
Serum Testosterone (ug/ml)
1.60
1.00 0.80
3.50
Initial
3.00
After 24 months
0.60
2.50
0.40 0.20
2.00
0.00 initial
6 months
12 months
18 months
A
24 months
B
C
Study Groups
Duration of Treatment
C: Mean After-load serum Insulin
D: Weight Change 105.00
250.00
95.00
Kg
90.00 85.00 Initial
80.00
After 24 months
75.00 70.00
Serum Insulin (uIU/L)
100.00 200.00
150.00
Initial After 24 months
100.00
50.00
65.00 0.00
60.00 A
B
C
Study Groups
A
B
C
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 interaction between androgens, insulin, and visceral obesity in PCOS [19–24]. The natural histories of the metabolic syndrome and hyperandrogenaemia, although inter-related at possibly multiple levels, may not be strictly interdependent; with hyperandrogenaemia showing a pre-pubertal rise, a steady course, even through pregnancy, and a pre-menopausal resolution [7]. The maintained hyperandrogenaemia, in the metformin group, despite significant weight loss and lower serum insulin levels, possibly indicates a more fundamental and stable driving mechanism for excessive androgen secretion, with hyperinsulinaemia as a mere exacerbating factor. Unlike its effect on hyperandrogenaemia, the beneficial effect of metformin on the metabolic syndrome [25], of which insulin resistance and body weight were taken as indices, continues to improve throughout the 2 year-follow up period of this study. In this context, initiation of insulin sensitizer therapy at such an early age appears to be an appropriate preventive measure [26]. However, the added advantage of correcting serum androgens, suggested by some trials, may be debatable [27–29]. This goal may be achieved by the adjunctive use of an antiandrogen which, although effective, needs to be justified in the long-term, as the existence of a correlation between hyperandrogenaemia per se and late cardiovascular complications in PCOS women is, so far, contradictory [6,30]. Furthermore, as confirmed in our study, insulin sensitizers alone seem to provide a level of patient satisfaction as regards hirsutism, which is comparable to oral contraceptives [11]. However, adjunctive anti-androgens may have a role in improving the results of fertility therapy [21,31–33].
Oral contraceptive pills have been a traditional long-term therapy for PCOS, to regulate menstrual cycle, protect the endometrium, and improve hirsutism and acne by reducing ovarian androgen production [11,34]. These proven advantages, however, may be counterbalanced by the obvious deterioration in insulin-resistance and body weight compared to the control group, as observed on follow up in our study. In addition to the potentially grave consequences associated with the acceleration of the metabolic component of PCOS, weight gain proves to be a particularly challenging side effect in the adolescent age group, effectively undermining patient compliance in the long term [21,35,11]. These facts, coupled with the recent evidence of the detrimental effects of oral contraceptives on the low-grade inflammatory state suspected to mediate atherosclerosis in PCOS patients [36], should warrant a degree of caution in prescribing oral contraceptives for these adolescents, on a long-term basis. If the main complaints are limited to acne and hirsutism, insulin-sensitizers are obviously advantageous, but if the main aim is menstrual cycle control, oral contraceptives have clear advantages in terms of effectiveness and cost. Their use with proper monitoring risk factors, or in conjunction with other modalities of therapy, including hypo-caloric restriction, exercise [23], insulin-sensitizers, and/ or an antiandrogen [21,31–33] may limit the risk of serious long-term complications [37,21,38,39,31–33]. The choice of the proper line of therapy should be tailored for every patient, according to her age, stage in life, presenting symptoms, various personal and familial risk indices, as well as her own informed choices. This study suggests that insulin sensitizers are a proper choice for adolescent PCOS women pre-
136 senting with acne and hirsutism, having a safer profile than combined oral contraceptives. 5. Capsule Metformin and COC have comparable therapeutic effectiveness on cycle regularity and hirsutism. Metformin was associated with significant weight loss and improvement in the metabolic syndrome, while COC was associated with non-significant weight gain and deterioration of the metabolic syndrome. Conflict of interest We have no conflict of interest to declare. References [1] Hassan A, Gordon CM. Polycystic ovary syndrome update in adolescence. Curr. Opin. Pediatr. 2007;19:389–97. [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;91:492–7. [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;87:1369–76. [4] Trent ME, Rich M, Austin SB, Gordon CM. Quality of life in adolescent girls with polycystic ovary syndrome. Arch. Pediatr. Adolesc. Med. 2002;156:556–60. [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 proinflammatory markers. Metabolism 2007;56:766–71. [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;88:1389–95. [7] Pasquali R, Gambineri A. Polycystic ovary syndrome: a multifaceted disease from adolescence to adult age. Ann. N.Y. Acad. Sci. 2006;1092:158–74. [8] Pasquali R, Patton L, Pagotto U, Gambineri A. Metabolic alterations and cardiovascular risk factors in the polycystic ovary syndrome. Minerva Ginecol. 2005;57:79–85. [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. Endocrinol. Metab. 2005;18:761–8. [10] Costello M, Shrestha B, Eden J, Sjoblom P, Johnson N. Insulinsensitising 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;22:1200–9. [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;87:1555–9. [13] Dokras A. Cardiovascular disease risk factors in polycystic ovary syndrome. Semin. Reprod. Med. 2008;26:39–44.
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