Middle East Fertility Society Journal (2011) 16, 175–181
Middle East Fertility Society
Middle East Fertility Society Journal www.mefsjournal.com www.sciencedirect.com
OPINION ARTICLE
The role of metformin in ovulation induction: Current status Aboubakr Mohamed Elnashar
*
Benha University Hospital, Benha, Egypt Received 10 August 2010; accepted 12 October 2010 Available online 13 April 2011
KEYWORDS PCOS; Metformin; Ovulation induction
Abstract To define the exact role of metformin in ovulation induction, it is crucial to distinguish three different indications: naı¨ ve PCOS, CC-resistant PCOS and ART. In naı¨ ve PCOS: metformin as compared to placebo has been shown to improve ovulation rates, but metformin did not exert significant advantage over CC with respect to cumulative ovulation, pregnancy or live-birth rates. The combined approach of metformin plus CC is not better than CC or metformin monotherapy in naı¨ ve PCOS. In CC-resistant patients: metformin has no benefit over placebo in ovulation, pregnancy, and live-birth rates as a single agent, but the combination of metformin and CC significantly improved ovulation and pregnancy rates when compared with CC alone. However, combined therapy did not improve the odds of live birth. Metformin pretreatment improves the efficacy of CC in PCOS patients with CC resistance. In PCOS patients scheduled for ART: metformin addition to gonadotropins reduces the duration of gonadotropins administration and the doses of gonadotropins required, and increases the rate of monoovulations, reducing the risk of cancelled cycles. Metformin co-administration to IVF treatment does not improve pregnancy or live-birth rates but reduces the risk of OHSS. Ó 2010 Middle East Fertility Society. Production and hosting by Elsevier B.V. All rights reserved.
1. Introduction The polycystic ovary syndrome (PCOS) is a common endocrinopathy, affecting 6.8% of reproductive-aged women (1). * Corresponding author. E-mail address:
[email protected] 1110-5690 Ó 2010 Middle East Fertility Society. Production and hosting by Elsevier B.V. All rights reserved. Peer review under responsibility of Middle East Fertility Society. doi:10.1016/j.mefs.2010.10.003
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Anovulation and androgen excess have been considered the hallmark diagnostic criteria of the syndrome. Insulin resistance (IR) has been identified as a significant contributor to the pathogenesis of PCOS. Metformin has been used alone or combined with CC in induction of ovulation. Its mechanism of action and role in ovulation induction will be discussed in three different indications: Naı¨ ve PCOS, CC-resistant PCOS and ART. Factors affecting response to metformin will be elaborated. 1.1. Insulin resistance IR has been demonstrated to participate in the reproductive as well as metabolic abnormalities associated with PCOS (2). IR is defined as a reduced glucose response to a given amount of insulin and usually results from faults within the insulin receptor and post-receptor signaling. IR and secondary hyperinsulinemia affect approximately 65–70% of women with PCOS (3).
176 Many of these women are also obese, which further exacerbates their IR. Insulin stimulates ovarian theca cell androgen production and secretion, and suppresses the hepatic production of sex hormone-binding globulin. The increased intraovarian androgens then disrupt folliculogenesis (4). Hyperinsulinemia may also directly cause premature follicular atresia and antral follicle arrest. The resulting anovulation also leads to unopposed estrogen production and endometrial proliferation in women with PCOS, leading to an increased risk of endometrial hyperplasia. Consistent with the high prevalence of IR and obesity, patients with PCOS demonstrate a greater prevalence of impaired glucose tolerance (IGT), type 2 DM, dyslipidemia, and chronic subclinical inflammation (5). Many patients with PCOS demonstrate features consistent with the metabolic (or dysmetabolic) syndrome. IR can be measured by a number of expensive and complex tests but in clinical practice it is not necessary to measure it routinely; it is more important to check for IGT (6). Simple screening tests include an assessment of body mass index (BMI) and waist circumference. If the fasting blood glucose is <5.2 mmol/l the risk of IGT is low. 1.2. Metformin Metformin is a biguanide currently used as an oral antihyperglycemic agent and is approved by the US Food and Drug Administration to manage type 2 DM. The benefits of metformin on insulin sensitivity have been demonstrated in non-DM women with PCOS. The use of metformin is associated with increased menstrual cyclicity, improved ovulation, and a reduction in circulating androgen levels (7). Metabolic benefits are enhanced in the presence of weight loss and weight loss itself may be enhanced in the presence of metformin (8). 1.2.1. Mechanism of action Its primary clinical action is to inhibit hepatic glucose production, although it also decreases intestinal glucose uptake and increases insulin sensitivity in peripheral tissues (9). Metformin likely plays its role in improving ovulation induction in women with PCOS through a variety of actions, including reducing insulin levels and altering the effect of insulin on ovarian androgen biosynthesis, theca cell proliferation, and endometrial growth. Also, potentially through a direct effect, it inhibits ovarian gluconeogenesis and thus reduces ovarian androgen production (10). Metformin has been shown to inhibit GnRH release by activation of hypothalamic AMPK, a crucial regulator of food intake in mammals, in a dose-dependent and timedependent fashion (11). 2. Role of metformin in ovulation induction Many studies involved small and phenotypically heterogeneous groups and did not draw any distinction between therapy-naive and clomiphene citrate (CC)-resistant women (12).To define the exact role of metformin in ovulation induction, it is crucial to distinguish three different indications: Naı¨ ve PCOS, CC-resistant PCOS and ART. 2.1. Naive PCOS patients 2.1.1. As single agent Metformin as compared to placebo has been shown to improve ovulation rates in women with PCOS in randomized
A.M. Elnashar controlled trials (RCTs), cohort studies, or uncontrolled descriptive studies. However, only few of them had pregnancy as a defined outcome measure (13). In a meta-analysis, metformin alone has been shown to have a significant benefit on inducing ovulation in women with PCOS, but there is limited evidence that it improves pregnancy rates (2). Recently, a systematic review and meta-analysis of the head-to-head RCTs available in literature was conducted to better define the efficacy of CC and metformin, alone or in combination, as a first-step approach in treating anovulatory infertility in PCOS patients (14). Pooling the data obtained from the studies comparing metformin to CC (15–17), metformin did not exert significant advantage over CC with respect to cumulative ovulation, pregnancy or live-birth rates. However, the most interesting findings were the significant heterogeneity detected for all reproductive end-points. Great heterogeneity in the protocol used and in the populations studied was found (18). 2.1.2. Combined with CC Three head-to-head RCTs (15,17,19) comparing reproductive efficacy of metformin plus CC combination vs. CC monotherapy in therapy-naive PCOS patients were available. Metformin plus CC was no more effective than CC alone in inducing ovulation in the study by Moll et al. (19) and by Zain et al. (17), whereas in the study by Legro et al. (15) the combination was significantly more effective than CC monotherapy. The pregnancy and live-birth rates were similar between metformin plus CC combination and CC monotherapy in the studies by Moll et al. (19), Legro et al. (15), and Zain et al. (17). When the data from these three studies were combined in a meta-analysis (14), the metformin plus CC association was shown to be no more effective than CC regarding rates of ovulation, pregnancy, or live births. A main drawback in the design of the RCTs that assessed the efficacy of combined CC plus metformin vs. CC (15,17,19) or metformin (15,17) alone was that metformin was started either concurrently with (15,17) or after only 1 month (19) of CC initiation. Metformin has a slower onset of action than CC; hence, the studies as such were unintentionally biased against demonstrating the value of the CC plus metformin combination. In conclusion, in anovulatory infertile therapy-naı¨ ve PCOS patients, the combined approach of metformin plus CC is not better than CC or metformin monotherapy. 2.2. CC-resistant PCOS patients 2.2.1. As single agent In small RCT (18 infertile women) (21) found no benefit of metformin over placebo in ovulation, pregnancy, and livebirth rates as a single agent in CC-resistant patients. In a study by Vandermolen et al. a significant improvement on both ovulation and pregnancy rates were observed in women with CCresistant PCOS who were treated with metformin alone. In RCT, Elnashar et al. demonstrated that metformin alone is an effective drug in inducing ovulation in CC-resistant PCOS, whereas N-acetyl cysteine alone is not (22). Palomba et al. (23) compared metformin as a single treatment with laparoscopic ovarian diathermy (LOD) in CC-resistant PCOS patients. No difference was present between metformin and LOD in the ovulation rate but significantly higher pregnancy and live-birth rates were observed.
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A successive meta-analysis (24) showed no evidence of difference in the clinical pregnancy rate, whereas the live-birth rate was still higher after metformin. However, metformin treatment was certainly not inferior to LOD and was about 20-fold less expensive than the surgical ovulation induction (23).
protein kinase (MAPK)3/MAPK1 phosphorylation through AMPK activation.
2.2.2. Combined with other treatment 2.2.2.1. With CC. The efficacy of metformin cotreatment in CC-resistant patients who received CC was evaluated in several studies (24–28). Two meta-analyses (25,26) agreed in demonstrating a significant benefit of metformin cotreatment in comparison with CC alone, even if a significant heterogeneity was observed between studies included in both meta-analyses. In particular, in CC-resistant PCOS women, the addition of metformin was demonstrated to be effective in inducing ovulation in the two meta-analyses by Lord et al. (25) and Kashyap et al. (26). In the same manner, significant benefits of the combination therapy on pregnancy rate were demonstrated in both studies. A successive meta-analysis (27), designed to assess metformin coadministration as a second-step approach for CC-resistant PCOS patients, confirmed that metformin plus CC is significantly more effective than CC alone in terms of ovulations, even if a significant heterogeneity was demonstrated across studies, and no data were provided regarding the effect on pregnancy and live-birth rates. Moll et al. (24) also compared metformin plus CC to CC alone in CC-resistant women and confirmed that metformin plus CC led to significantly higher clinical pregnancy and live-birth rates without significant heterogeneity in treatment effect across trials. In a meta-analysis of placebo-controlled RCTs only, the combination of metformin and CC significantly improved ovulation and pregnancy rates when compared with CC alone (28). However, combined therapy did not improve the odds of live birth. Furthermore, a significant heterogeneity was detected between all studies included in the analysis. Conversely, metformin did not have any effect on live births and no significant heterogeneity data were present. The results suggested combination therapy (metformin plus CC) as the treatment of choice in CC-resistant women. The combination of metformin plus CC was demonstrated to be more effective than LOD in CC-resistant PCOS patients with anovulatory infertility (29). In particular, metformin plus CC association was related to higher ovulation rates than LOD, even if no difference in the rates of pregnancies, live births and miscarriages were detected between two procedures (29). Despite the lack of convincing data that metformin improves live-birth rates; there may be value in attempting this treatment prior to proceeding to more expensive and invasive therapies, such as LOD or low-dose gonadotropins (21). Metformin therapy would augment the induction of ovulation in CC-resistant women because of its favorable change in androgens, gonadotropins, and insulin, through mechanisms distinct from those of CC (21). It is plausible to assume that women with CC resistance receiving metformin have an increased response to CC secondary to an intrinsic alteration of the microenvironment of the follicle caused by the effect of metformin pretreatment on insulin and the insulin growth factor (IGF)-I pathway in granulose cells (29). More specifically, Tosca et al. (31) reported that in bovine granulose cells, metformin decreases steroidogenesis and mitogen-activated
2.2.2.2. With letrozole. Adding metformin to CC in clomiphene-resistant PCOS patients increases ovulatory response. However, because of anti-estrogenic effects of CC it may be associated with lower pregnancy rate, offsetting the ovulation rate benefit. Letrozole is an aromatase inhibitor which induces ovulation without anti-estrogenic effects. Small RCT was done by Sohrabvand et al. in 2006, (32) comparing addition of letrozole or CC to metformin clomiphene-resistant PCOS patients. After an initial 6–8 weeks of metformin, they received either letrozole (2.5 mg) or CC (100 mg) from day 3–7 of their menstrual cycle. No difference in mean number of mature follicles >18 mm and ovulation rate was found. However, endometrial thickness and full-term pregnancies were significantly higher in patients treated with metformin plus letrozole (32). 2.2.2.3. With LOD. In one trial (33) CC-resistant PCOS patients were randomized to LOD followed by metformin or LOD alone. Ovulation (86.1% vs. 44.6%) and pregnancy (47.6% vs. 19.1%) rates were significantly higher in patients who received metformin. Furthermore, a successive meta-analysis (24) demonstrated no significant benefit in clinical pregnancy rate for the metformin administration after LOD. 2.2.3. Metformin pretreatment Several RCTs (34–39) evaluated the efficacy of metformin pretreatment before CC in CC-resistant PCOS patients. Even if these studies were very heterogeneous and were performed on small populations, most of them (34–37) suggest that metformin pretreatment improves the efficacy of CC in PCOS patients with CC resistance. In particular, one small RCT (38) showed no beneficial effect on ovulation and pregnancy rates after 3 months of metformin pretreatment, despite the improvement of IR and hyperandrogenemia. On the contrary, other studies (34–37,39) demonstrated that metformin pretreatment, also when given in ultrashort protocols (37,39), improved CC response in terms of ovulation and pregnancy in CC-resistant PCOS patients. These findings support the idea that decreasing insulin secretion while administering metformin in PCOS patients facilitates the induction of ovulation by using CC (40). 2.3. PCOS patients scheduled for ART 2.3.1. Metformin, gonadotropins, and intrauterine insemination cycles A meta-analysis done by Costello et al. demonstrated that the co-administration of metformin to gonadotrophin does not significantly improve ovulation or pregnancy rates, whereas no RCT reporting live births as an outcome measure was identified (41). On the other hand, metformin was shown to be significantly efficient in reducing the length of time for ovarian stimulation while using gonadotropin and the total dose of FSH used. Two RCTs (42,43) evaluating whether metformin changes ovarian responsiveness in controlled ovarian stimulation cycles were recently published. The first RCT (42) on 70 non obese insulin-resistant PCOS patients who received a low-dose step-up gonadotropin stimulation protocol followed by timed intercourse or intrauterine insemination demonstrated a
178 significant effect of metformin in increasing the rate of monoovulatory cycles and in reducing those of cancelled cycles. Furthermore, no effect of metformin pretreatment and coadministration was confirmed in ovulation, cycle cancellation, pregnancy, abortion, live births, multiple pregnancies, or OHSS. The latter study (43) showed that metformin improved the endocrine profile in insulin-resistant PCOS patients receiving gonadotropins in a step-up protocol and confirmed that it facilitated the monofollicular development during ovarian stimulation cycles. Metformin may act on the regulation of ovarian response to exogenous gonadotropins improving insulin resistance. A reduction in serum testosterone and insulin levels in follicular fluid was observed after metformin treatment (44). Thus, the improvement of the hyperinsulinemic and hyperandrogenic ovarian environment might be crucial for a normal folliculogenesis, homogeneous development, and responsiveness of follicles and atresia of the small cohort of follicles (45). A recent meta-analysis by Moll et al., on four RCTs demonstrated a pooled clinical pregnancy rate that was significantly higher when metformin was added to gonadotropins than with gonadotropins alone (46). However, no significant difference in live-birth rate could be proven. In addition, metformin was demonstrated to be effective in reducing multiple pregnancies, whereas no difference in OHSS was reported. The lack of an effect of metformin on this end-point was probably due to the low incidence of OHSS during ovarian stimulation with low-dose step-up gonadotropin protocols (47). On the other hand, the employment of a step-up low dose protocol tailoring the gonadotropin administration seems to be a pivotal factor more and more in PCOS patients who receive metformin because metformin coadministration has been shown to increase the incidence of multiple pregnancies in patients who receive gonadotropins (48). In conclusion, in patients who received gonadotropins as treatment for anovulation, metformin addition reduces the duration of gonadotropins administration and the doses of gonadotropins required and increases the rate of monoovulations, reducing the risk of cancelled cycles. 2.3.2. Metformin and in vitro fertilization A meta-analysis of RCT on the effects of metformin co-treatment in women with PCOS undergoing IVF, reported that a 28-day course of metformin during the IVF cycle improves the pregnancy outcome, higher rates of ongoing pregnancy per cycle and per transfer and reduces the risk of OHSS. It failed to improve the response to stimulation and the fertilization rate (49). This finding is supported by a case-controlled study that also reported an increase in the pregnancy rate and a highly significant increase of embryo quality with metformin (50). Addition of metformin to FSH treatment for CC-resistant patients with PCOS has been reported to reduce serum levels of vascular endothelial growth factor (VEGF), the number of preovulatory follicles and the peak level of E2 (51). VEGF through the stimulation of ovarian angiogenesis may be a key mediator of OHSS. However, not all data support even this beneficial effect of metformin during IVF in patients with PCOS. Data obtained from two meta-analyses (41,46) suggest that metformin did not improve the efficacy of gonadotropins when it was prescribed in the context of adjuvant treatment for IVF cycles. In particular, Costello et al. (41) analyzed four published
A.M. Elnashar RCTs and one trial published in abstract format only evaluating the effect of metformin addition to gonadotropins in women undergoing IVF cycles. Metformin was demonstrated to have no significant effect on the number of oocytes collected at IVF, length of ovarian stimulation, pregnancy and live-birth rates. A significant decrease in the total dose of gonadotropins used during IVF cycles and in OHSS risk was shown by Costello et al. (41). Pooling the data of the two trials that reported multiple pregnancies gave no evidence of a significant difference between the two groups on multiple pregnancies’ rates. On the basis of these results, some authors concluded that to date no adjuvant pretreatment in IVF cycles should be suggested in the clinical practice (52). Metformin co-administration to IVF treatment does not improve pregnancy or live-birth rates but reduces the risk of OHSS. The OHSS is the most serious complication of IVF in women with PCOS and may lead to catastrophic complications and even death. 3. Factors affecting response to metformin Reflecting the clinical and pathophysiologic heterogeneity of PCOS, treatment with metformin can elicit variable results, ranging from no response to moderate or significant improvement (53). Phenotypes of PCOS with distinct endocrine and metabolic features may be differentially affected by metformin therapy. However, the determinants of response to metformin therapy in women with PCOS remain enigmatic (7). Despite the lack of clear-cut evidence, clinical studies have attempted to identify predictors of response to metformin. Interestingly, favorable metabolic changes are often paralleled by reproductive improvement in treated patients. This observation is compatible with the fact that both the metabolic and the reproductive effects of metformin depend, to a large extent, on the alleviation of IR. 3.1. Baseline BMI Baseline BMI was confirmed as a major predictor of both ovulation and pregnancy under metformin treatment in women with PCOS. Higher BMIs appear to be associated with suboptimal therapeutic results of metformin regarding metabolic as well as reproductive abnormalities. It is commonly experienced that obese women, particularly those with morbid obesity, are refractory to metformin therapy (54). Obesity counteracts the attenuation of IR induced by metformin. This adverse interaction compromises the overall therapeutic efficacy of the drug, including both metabolic and reproductive aspects (2,55). Advanced age and longer duration of infertility had an adverse impact on pregnancy response under metformin. 3.2. Insulin-resistant PCOS Insulin-resistant PCOS patients with low BMI were reported to be more likely to respond to metformin, whereas CC treatment was more effective in less hyperandrogenic and more insulin-sensitive patients with low BMI (56). However, previous studies did not confirm the predictive value of IR indices for ovulation induction by metformin (57). This discrepancy may reside in the use of surrogate mathematical indices for the assessment of IR. Alternatively, the dissociation between the improvement of insulin sensitivity and the restoration of
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ovulation implicates other mechanisms, independent of insulin, in the reproductive response to metformin. For example, metformin may be able to directly affect ovarian steroidogenesis (58). In addition, this drug could affect the central regulation of ovulation by modulating GnRH release through the activation of the hypothalamic AMPK (11). The degree of IR may be a factor in deciding whether or not to add metformin to the cycle regimen until the pregnancy test. Chang et al. (59) showed that the insulin levels and the degree of beta-cell function (as measured by homeostasis assessment model [HOMA] beta-cell percent) are highest in oligoovulatory women with PCOS who are both hirsute and hyperandrogenemic, as compared with patients with PCOS who are either hyperandrogenemic or hirsute only. In this regard, a greater improvement in effectiveness (defined as decreases in luteinizing hormone [LH], estradiol, insulin, and C-peptide) was observed among women with PCOS who were both hyperandrogenic and hyperinsulinemic (60).
(a) CC resistance (24) or those who are older and viscerally obese (55). The ability of metformin to restore responsiveness to CC in obese women with PCOS and the low rates of multiparity and ovarian hyperstimulation syndrome (OHSS) are additional potential benefits of metformin therapy in the CC-resistant patient. (b) Metformin appears to be a useful tool in women with longer timelines for achieving pregnancy (65). For those women with a short term but not immediate desire for pregnancy, consideration should be given to pretreatment with metformin before prescribing CC for ovulation induction. This option may allow metformin to develop its full reproductive and metabolic efficacy since its onset of action is known to be gradual. In these cases, pretreatment of obese patients with metformin combined with lifestyle modification may result in weight loss, which reduces the likelihood of clomiphene resistance and the risk for gestational or obstetrical complications (66). (c) Glucose intolerance: the recent ‘Thessaloniki consensus paper’ recommended that metformin use in PCOS should be restricted to women with glucose intolerance (67).
3.3. Androgen level The degree of androgen excess may be another determinant of the reproductive efficacy of metformin. In studies evaluating the posttreatment ovulation rate (57), responders to metformin were less hyperandrogenic than nonresponders.
4. Conclusion
3.4. Genotype The role of the genotype is also currently explored. In a prospective randomized trial, a specific polymorphism in STK11 (also known as LKB1), a kinase gene expressed in liver and implicated in metformin’s action, was associated with ovulatory response to treatment with metformin (61). 3.5. Menstrual abnormalities Moghetti et al. (62) performed a logistic regression analysis of baseline characteristics in patients with PCOS who responded (i.e., had an improvement in menstrual bleeding frequency) or who did not respond to metformin treatment after receiving 1500 mg/day for 11.0 ± 1.3 months (open trial; range 4–26 months). The researchers observed that higher plasma insulin, lower serum androstenedione, and less severe menstrual abnormalities were independent predictors of clinical efficacy of metformin. 3.6. The length of metformin administration In meta-analytic studies (13,24,26,28,63,27), the beneficial effect of metformin could be diluted in time with longer followup periods due to more time available for spontaneous ovulation in control group patients. On the other hand, short-course metformin (<4 weeks) could be a suboptimal pretreatment period before beginning CC. Unfortunately, there presently is no RCT assessing this aim, and there is insufficient data to determine whether long-course metformin pretreatment, before initiation of CC for ovulatory infertility treatment, is more effective than short-course pretreatment (64). 3.7. Specific subgroups Although CC is recognized as the first-line agent in women with PCOS who desire immediate pregnancy, addition of metformin may be beneficial to specific subgroups:
(1) In naı¨ ve PCOS: metformin as compared to placebo has been shown to improve ovulation rates, but metformin did not exert significant advantage over CC with respect to cumulative ovulation, pregnancy or live-birth rates. The combined approach of metformin plus CC is not better than CC or metformin monotherapy. (2) In CC-resistant patients: metformin has no benefit over placebo in ovulation, pregnancy, and live-birth rates as a single agent, but the combination of metformin and CC significantly improved ovulation and pregnancy rates when compared with CC alone. However, combined therapy did not improve the odds of live birth. Metformin pretreatment improves the efficacy of CC in PCOS patients with CC resistance. (3) In PCOS patients scheduled for ART: metformin addition to gonadotropins reduces the duration of gonadotropins administration and the doses of gonadotropins required, and increases the rate of monoovulations, reducing the risk of cancelled cycles. Metformin coadministration to IVF treatment does not improve pregnancy or live-birth rates but reduces the risk of OHSS. References (1) Diamanti-Kandarakis E, Kouli CR, Bergiele AT, Filandra FA, Tsianateli TC, Spina GG, Zapanti ED, Bartzis MI. A survey of the polycystic ovary syndrome in the Greek island of Lesbos: hormonal and metabolic profile. J Clin Endocrinol Metab 1999;84:4006–411. (2) Legro RS, Barnhart HX, Schlaff WD, Carr BR, Diamond MP, Carson SA, et al.Cooperative Multicenter Reproductive Medicine Network. Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome. N Engl J Med 2007;356:551–66. (3) DeUgarte CM, Barolucci AA, Azziz R. Prevalence of insulin resistance in the polycystic ovary syndrome using the homeostasis model assessment. Fertil Steril 2005;83:1454–60.
180 (4) Jonard S, Dewailly D. The follicular excess in polycystic ovaries, due to intra-ovarian hyperandrogenism, may be the main culprit for the follicular arrest. Hum Reprod Update 2004;10:107–17. (5) Ehrmann DA. Polycystic ovary syndrome. N Engl J Med 2005;352:1223–36. (6) Legro RS, Castracane VD, Kauffman RP. Detecting insulin resistance in polycystic ovary syndrome: purposes and pitfalls. Obstet Gynecol Surv 2004;59:141–54. (7) Nestler JE. Metformin for the treatment of the polycystic ovary syndrome. N Engl J Med 2008;358:47–54. (8) Tan S, Hahn S, Benson S, et al.. Metformin improves polycystic ovary syndrome symptoms irrespective of pre-treatment insulin resistance. Eur J Endocrinol 2007;157:669–76. (9) Yildiz BO, Knochenhauer ES, Azziz R. Impact of obesity on the risk for polycystic ovary syndrome. J Clin Endocrinol Metab 2008;93:162–8. (10) Barbieri RL. Clomiphene versus metformin for ovulation induction in polycystic ovary syndrome. Clin Endocrinol Metab 2007;92:3399–401. (11) Coyral-Castel S, Tosca L, Ferreira G, Jeanpierre E, Rame C, Lomet D, Caraty A, Monget P, Chabrolle C, Dupont J. The effect of AMP-activated kinase activation on gonadotrophin-releasing hormone secretion in GT1–7 cells and its potential role in hypothalamic regulation of the oestrous cyclicity in rats. J Neuroendocrinol 2008;20:335–46. (12) Johnson NP. No more surrogate end-points in randomised trials: the PCOSMIC trial protocol for women with polycystic ovary syndrome using metformin for infertility with clomiphene. Aust NZ J Obstet Gynaecol 2006;46:141–5. (13) Lord JM, Flight IH, Norman RJ. Metformin in polycystic ovary syndrome: systematic review and meta-analysis. BMJ 2003;327:951–3. (14) Palomba S, Pasquali R, Orio F, Nestler JE. Clomiphene citrate, metformin or both as first-step approach in treating anovulatory infertility in patients with polycystic ovary syndrome (PCOS): a systematic review and meta-analysis. Clin Endocrinol 2008;10:1365–85. (15) Legro RS, Barnhart HX, Schlaff WD, Carr BR, Diamond MP, Carson SA, Steinkampf MP, Coutifaris C, McGovern PG, Cataldo NA, Gosman GG, Nestler JE, Giudice LC, Leppert PC, Myers ERCooperative Multicenter Reproductive Medicine Network 2007. Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome. N Engl J Med 2007;356:551–6. (16) Palomba S, Orio Jr F, Falbo A, Manguso F, Russo T, Cascella T, Tolino A, Carmina E, Colao A, Zullo F. Prospective parallel randomized, double-blind, double-dummy controlled clinical trial comparing clomiphene citrate and metformin as the first-line treatment for ovulation induction in non obese anovulatory women with polycystic ovary syndrome. J Clin Endocrinol Metab 2005;90:4068–74. (17) Zain MM, Jamaluddin R, Ibrahim A, Norman RJ. Comparison of clomiphene citrate, metformin, or the combination of both for first-line ovulation induction, achievement of pregnancy, and live birth in Asian women with polycystic ovary syndrome: a randomized controlled trial. Fertil Steril 2007;10:1016–21. (18) Palomba S, Orio Jr F, Zullo F. What is the best first-step therapeutic approach in treating anovulatory infertility in patients with polycystic ovary syndrome? Questions that are still unanswered. Gynecol Endocrinol 2007;23:245–7. (19) Moll E, Bossuyt PM, Korevaar JC, Lambalk CB, van der Veen F. Effect of clomifene citrate plus metformin, clomifene citrate plus placebo on induction of ovulation in women with newly diagnosed polycystic ovary syndrome: randomised double blind clinical trial. BMJ 2006;332:1485. (21) Vandermolen DT, Ratts VS, Evans WS, Stoval DW, Kauma SW, Nestler JE. Metformin increases the ovulatory rate and pregnancy rate from clomiphene citrate in patients with polycystic ovary
A.M. Elnashar
(22)
(23)
(24)
(25)
(26)
(27)
(28)
(29)
(31)
(32)
(33)
(34)
(35)
(36)
(37)
(38)
syndrome who are resistant to clomiphene citrate alone. Fertil Steril 2001;75:310–5. Elnashar A, Fahmy M, Mansour A, Ibrahim K. N-acetyl cysteine versus metformin in treatment of clomiphene citrate resistant polycystic ovary syndrome: a prospective randomized controlled study. Fertil Steril 2007;88:406–9. Palomba S, Orio Jr F, Nardo LG, Falbo A, Russo T, Corea D, Doldo P, Lombardi G, Tolino A, Colao A, Zullo F. Metformin administration versus laparoscopic ovarian diathermy in clomiphene citrate-resistant women with polycystic ovary syndrome: a prospective parallel randomized double-blind placebo-controlled trial. J Clin Endocrinol Metab 2004;89:4801–9. Moll E, van der Veen F, Van Wely M. The role of metformin in polycystic ovary syndrome: a systematic review. Hum Reprod Update 2007;13:527–37. Lord JM, Flight IH. Norman RJ 2003 Metformin in polycystic ovary syndrome: systematic review and meta analysis. BMJ 2003;327:951–3. Kashyap S, Wells GA, Rosenwaks Z. Insulin-sensitizing agents as primary therapy for patients with polycystic ovarian syndrome. Hum Reprod 2004;19:2474–83. Siebert TI, Kruger TF, Steyn DW, Nosarka S. Is the addition of metformin efficacious in the treatment of clomiphene citrate resistant patients with polycystic ovary syndrome? A structured literature review. Fertil Steril 2006;86:1432–7. Creanga AA, Bradley HM, McCormick C, Witkop CT. Use of metformin in polycystic ovary syndrome: a meta-analysis. Obstet Gynecol 2008;111:959–68. Palomba S, Falbo A, Battista L, Russo T, Venturella R, Tolino A, Orio F, Zullo F. Laparoscopic ovarian diathermy versus metformin plus clomiphene citrate administration as second-line strategy for infertile anovulatory patients with polycystic ovary syndrome: a randomized controlled trial. Am J Obstet Gynecol 2010;202:577. Tosca L, Chabrolle C, Svetlana U, Dupont J. Effects of metformin on bovine granulose cells steroidogenesis: possible involvement of adenosine 50 monophosphate-activated protein kinase (AMPK). Biol Reprod 2007;76:368–78. Sohrabvand F, Ansari SH, Bagheri M. Efficacy of combined metformin-letrozole in comparison with metformin-clomiphene citrate in clomiphene-resistant infertile women with polycystic ovarian disease. Hum Reprod 2006;21:1432–5. Kocak I, Ustun C. Effects of metformin on insulin resistance, androgen concentration, ovulation and pregnancy rates in women with polycystic ovary syndrome following laparoscopic ovarian drilling. J Obstet Gynaecol Res 2006;32:292–8. George SS, George K, Irwin C, Job V, Selvakumar R, Jeyaseelan V, Seshadri MS. Sequential treatment of metformin and clomiphene citrate in clomiphene-resistant women with polycystic ovary syndrome: a randomized, controlled trial. Hum Reprod 2003;18:299–304. Nestler JE, Jakubowicz DJ, Evans WS, Pasquali R. Effects of metformin on spontaneous and clomiphene-induced ovulation in the polycystic ovary syndrome. N Engl J Med 1998;338:1876–80. Palomba S, Orio Jr F, Falbo A, Russo T, Caterina G, Manguso F, Tolino A, Colao A, Zullo F. Metformin administration and laparoscopic ovarian drilling improve ovarian response to clomiphene citrate (CC) in oligo-anovulatory CC-resistant women with polycystic ovary syndrome. Clin Endocrinol (Oxf) 2005;63:631–5. Khorram O, Helliwell JP, Katz S, Bonpane CM, Jaramillo L. Two weeks of metformin improves clomiphene citrate-induced ovulation and metabolic profiles in women with polycystic ovary syndrome. Fertil Steril 2006;85:1448–51. Sturrock ND, Lannon B. Fay TN 2002 Metformin does not enhance ovulation induction in clomiphene resistant polycystic ovary syndrome in clinical practice. Br J Clin Pharmacol 2002;53:469–73.
The role of metformin in ovulation induction: Current status
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(39) Hwu YM, Lin SY, Huang WY, Lin MH, Lee RK. Ultra-short metformin pretreatment for clomiphene citrate-resistant polycystic ovary syndrome. Int J Gynaecol Obstet 2005;90:39–43. (40) Palomba S, Falbo A, Orio F, Zullo F. Insulin sensitizing agents and reproductive function in polycystic ovary syndrome patients. Curr Opin Obstet Gynecol 2008;20:364–73. (41) Costello MF, Chapman M, Conway U. A systematic review and meta-analysis of randomized controlled trials on metformin coadministration during gonadotrophin ovulation induction or IVF in women with polycystic ovary syndrome. Hum Reprod 2006;21:1387–99. (42) Palomba S, Falbo A, Orio Jr F, Manguso F, Russo T, Tolino A, Colao A, Dale B, Zullo F. A randomized controlled trial evaluating metformin pre-treatment and co-administration in nonobese insulin-resistant women with polycystic ovary syndrome treated with controlled ovarian stimulation plus timed intercourse or intrauterine insemination. Hum Reprod 2005;20:2879–86. (43) van Santbrink EJ, Hohmann FP, Eijkemans MJ, Laven JS, Fauser BC. Does metformin modify ovarian responsiveness during exogenous FSH ovulation induction in normogonadotrophic anovulation? A placebo-controlled double-blind assessment. Eur J Endocrinol 2005;152:611–7. (44) Stadtmauer LA, Toma SK, Riehl RM, Talbert LM. Metformin treatment of patients with polycystic ovary syndrome undergoing in vitro fertilization improves outcomes and is associated with modulation of the insulin-like growth factors. Fertil Steril 2001;75:505–9. (45) Palomba S, Falbo A, Fulvio Zullo F, Orio F. Evidence-based and potential benefits of metformin in the polycystic ovary syndrome: a comprehensive review. Endocr Rev 2009;30:1–50. (46) Moll E, van der Veen F, van Wely M. The role of metformin in polycystic ovary syndrome: a systematic review. Hum Reprod Update 2007;13:527–37. (47) Gorry A, White DM, Franks S. Infertility in polycystic ovary syndrome: focus on low-dose gonadotropin treatment. Endocrine 2006;30:27–33. (48) Shibahara H, Kikuchi K, Hirano Y, Suzuki T, Takamizawa S, Suzuki M. Increase of multiple pregnancies caused by ovulation induction with gonadotropin in combination with metformin in infertile women with polycystic ovary syndrome. Fertil Steril 2007;87:1487–90. (49) Tang T, Glanville J, Orsi N, Barth JH, Balen AH. The use of metformin for women with PCOS undergoing IVF treatment. Hum Reprod 2006;21:1416–25. (50) Stadtmauer LA, Toma SK, Reihl RM, Talbert LM. Metformin treatment of patients with polycystic ovary syndrome undergoing in vitro fertilization improves outcomes and is associated with modulation of the insulin like growth factors. Fertil Steril 2001;75:505–9. (51) De Leo V, la Marca A, Ditto A, Morgante G, Cianci A. Effects of metformin on gonadotropin-induced ovulation in women with polycystic ovary syndrome. Fertil Steril 1999;72:282–5. (52) Bromer JG, Cetinkaya MB, Arici A. Pretreatments before the induction of ovulation in assisted reproduction technologies: evidence- based medicine in 2007. Ann N Y Acad Sci 2008;1127:31–40. (53) Diamanti-Kandarakis E, Christakou C, Kandaraki E, Economou F. Metformin: an old medication of new fashion: evolving new molecular mechanisms and clinical implications in polycystic ovary syndrome. Eur J Endocrinol 2010;162:193–212.
(54) Tang T, Glanville J, Hayden CJ, White D, Barth JH, Balen AH. Combined lifestyle modification and metformin in obese patients with polycystic ovary syndrome. A randomized, placebocontrolled, double-blind multicentre study. Hum Reprod 2006;21:80–9. (55) Maciel GA, Soares Junior JM, Alves da Motta EL, Abi Haidar M, de Lima GR Baracat EC. Nonobese women with polycystic ovary syndrome respond better than obese women to treatment with metformin. Fertil Steril 2004;81:355–60. (56) Palomba S, Falbo A, Orio Jr F, Tolino A, Zullo F. Efficacy predictors for metformin and clomiphene citrate treatment in anovulatory infertile patients with polycystic ovary syndrome. Fertil Steril 2008;91:2557–67. (57) Fleming R, Hopkinson ZE, Wallace AM, Greer IA Sattar N. Ovarian function and metabolic factors in women with oligomenorrhea treated with metformin in a randomized double blind placebo-controlled trial. J Clin Endocrinol Metab 2002;87:569–74. (58) Mansfield R, Galea R, Brincat M, Hole D Mason H. Metformin has direct effects on human ovarian steroidogenesis. Fertil Steril 2003;79:956–62. (59) Chang WY, Knochenhauer ES, Bartolucci AA, Azziz R. Phenotypic spectrum of polycystic ovary syndrome: clinical and biochemical characterization of the three major clinical subgroups. Fertil Steril 2005;83:1717–23. (60) Genazzani AD, Lanzoni C, Ricchieri F, Baraldi E, Casarosa E, Jasonni VM. Metformin administration is more effective when nonobese patients with polycystic ovary syndrome show both hyperandrogenism and hyperinsulinemia. Gynecol Endocrinol 2007;23:146–52. (61) Legro RS, Barnhart HX, Schlaff WD, Carr BR, Diamond MP, Carson SA, Steinkampf MP, Coutifaris C, McGovern PG, Cataldo NA, Gosman GG, Nestler JE, Giudice LC, Ewens KG, Spielman RS, Leppert PC, Myers ERReproductive Medicine Network. Ovulatory response to treatment of polycystic ovary syndrome is associated with a polymorphism in the STK11 gene. Reproductive Medicine Network 2007. J Clin Endocrinol Metab 2008;93:792–800. (62) Moghetti P, Castello R, Negri C, et al.. Metformin effects on clinical features, endocrine and metabolic profiles, and insulin sensitivity in polycystic ovary syndrome: a randomized, doubleblind, placebo-controlled 6-month trial, followed by open, longterm clinical evaluation. J Clin Endocrinol Metab 2000;85:139–46. (63) Costello MF, Eden JA. Asystematic review of the reproductive system effects of metformin in patients with polycystic ovary syndrome. Fertil Steril 2003;79:1–13. (64) Sinawat S, Buppasiri P, Lumbiganon P, Pattanittum P. Long versus short course treatment with metformin and clomiphene citrate for ovulation induction in women with PCOS. Cochrane Database Syst Rev 2008:CD006226. (65) Nestler JE. Metformin in the treatment of infertility in polycystic ovarian syndrome: an alternative perspective. Fertil Steril 2008;90:14–6. (66) Moll E, van der Veen F, van Wely M. The role of metformin in polycystic ovary syndrome: a systematic review. Hum Reprod Update 2007;13:527–37. (67) Thessaloniki ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Consensus on infertility treatment related to polycystic ovary syndrome. Fertil Steril 2008;89:505–22.