The role of metformin in ovulation induction: Current status

To define the exact role of metformin in ovulation induction, it is crucial to distinguish three different indications: naïve PCOS, CC-resistant PCOS and ART. In naïve 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 naïve 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.     

Coadministration of metformin or spironolactone enhances efficacy of rosiglitazone in management of PCOS

Abstract

The aim of this study was to compare the efficacy and safety of adding metformin or spironolactone to rosiglitazone in women with polycystic ovary syndrome (PCOS). This is a prospective non-randomized study in a tertiary care with at in a tertiary care endocrine clinic. Women (n?=?138) diagnosed with PCOS on the basis of Rotterdam criteria 2003 were categorized into three groups on the basis of drug intake as – rosiglitazone (R), rosiglitazone with spironolactone (R?+?S), and rosiglitazone with metformin (R?+?M). Clinical, biochemical, hormonal, and insulin sensitivity parameters were assessed at baseline and after six months of follow up. There was a significant improvement in number of menstrual cycles per year and Ferriman Gallwey (FG) score in all three groups after 6 months. Plasma insulin (0, 2?h), HOMA-IR and serum total testosterone levels decreased after six months in all the three groups. The inter group comparison showed higher efficacy of R?+?S in improving hyperandrogenism whereas R?+?M was most effective in decreasing body weight and plasma insulin levels compared to R and R?+?S (p<.05). Treatment of women with PCOS using rosiglitazone alone and in combination with spironolactone or metformin is safe and efficacious with limited adverse events however randomized trials with longer duration of follow up are warranted.     

Comparison of metformin plus myoinositol vs metformin alone in PCOS women undergoing ovulation induction cycles: randomized controlled trial

Abstract

The present study was planned to evaluate the benefit of synergetic effect of Metformin plus Myo-inositol versus Metformin alone in infertile polycystic ovarian syndrome (PCOS) women undergoing ovulation induction. One hundred and twenty infertile PCOS women were randomized: Group I (n?=?60) received Metformin (500?mg) plus Myoinositol(600?mg) three times a day; Group II received Metformin 500?mg three times a day. Subjects were advised to try for spontaneous conception. Those who did not conceive after 3?months, were given three cycles of ovulation induction?+?intrauterine insemination. Hormonal and biochemical profile parameters were done at baseline and after 3?months of therapy. Primary outcome measure was live birth rate. Secondary outcomes were improvement in menstrual cycle, hormonal and biochemical parameters, spontaneous conception, abortions, multiple pregnancy, and ovarian hyperstimulation syndrome. Baseline demographic, hormonal and biochemical parameters were comparable in two groups. There was a significant improvement in menstrual cycles (cycle length and bleeding days) in Group I as compared to Group II. The improvement in biochemical and hormonal parameters were comparable in the two groups after 3 months. Live birth rate was significantly higher in the Group I as compared to Group II [55% (33/60); 26.67% (16/60); p?=?.002]. The study concluded significantly higher live birth rate in women receiving the combination as compared to metformin alone.     

Role of phyto-oestrogens in ovulation induction in women with polycystic ovarian syndrome

Objective

To study the role of a phyto-oestrogen, Cimicifuga racimosa extract (Klimadynon^®, Bionorica, Neumarkt i.d.OBf., Germany), in ovulation induction in women with polycystic ovarian syndrome (PCOS).

Study design

Prospective randomized controlled trial in Minia University Hospital, Minia, Egypt. One hundred women with PCOS were allocated into one of two groups: one group (n = 50) received clomiphene citrate 100 mg daily for 5 days, and the other group (n = 50) received C. racimosa 20 mg daily for 10 days. Both groups received medication starting from the second day of the cycle for three consecutive cycles, during which changes in follicle-stimulating hormone (FSH), luteinizing hormone (LH), FSH/LH ratio, progesterone, endometrial thickness and pregnancy rate were measured.

Results

The groups were similar in terms of age, clinical presentation and hormonal levels before treatment. Following treatment, significant favourable changes in LH level and FSH/LH ratio (p = 0.007 and 0.06, respectively) were seen in the Klimadynon group. In this group the progesterone level was higher from the first treatment cycle, indicating better ovulation (p = 0.0001), and endometrial thickness was greater (p = 0.0004). The pregnancy rate was higher in the Klimadynon group but the difference between the groups was not significant (p = 0.1).

Conclusion

Phyto-oestrogen can be used as an alternative to clomiphene citrate for ovulation induction in women with polycystic ovarian syndrome.     

Laparoscopic ovarian drilling for women with anovulatory polycystic ovarian syndrome: a district general hospital experience

This is a retrospective study involving 100 anovulatory women with polycystic ovarian syndrome (PCOS) who had laparoscopic ovarian drilling (LOD) between January 1995 and May 2002 at the Royal Berkshire Hospital, Reading, a large district general hospital (DGH). The aim was to evaluate the efficacy of LOD in the treatment of women with anovulatory PCOS in a DGH setting. We also looked at the factors predicting the clinical outcome to be able to counsel the patients pre-operatively. The study showed that the spontaneous pregnancy rate after LOD was 32.46%. A further 28.5% conceived after induction of ovulation with clomiphene citrate (CC) or purified follicular stimulating hormone (Metrodin HP), with a cumulative pregnancy rate of 74%. We did not find a significant difference in the luteinising hormone to follicular stimulating hormone (LH:FSH) ratio of greater than 2.5, LH level of greater than 10 IU/l, body mass index (BMI), age or duration of infertility between the group of women who conceived and those who failed to conceive, in response to LOD.     

The effectiveness of metformin ovulation induction treatment in patients with PCOS: a systematic review and meta-analysis

Objective: To evaluate of metformin effectiveness of ovulation induction treatment in polycystic ovary syndrome (PCOS) women. Methods: Eight databases and nine related journals were searched for randomized controlled trails (RCTs) on the comparison between metformin and clomiphene citrate used for PCOS women. Meta analysis was performed after quality assessment. Results: Ovulation rate in metformin group compared with clomiphene citrate group was lower with a significant difference [OR = 0.48 (0.26–0.87), p = 0.01]; no significant difference was found for pregnancy rate [OR = 0.94 (0.26–3.43)], miscarriage rate [OR = 0.63 (0.06–6.47)] between two groups. Compared with the combination of metformin and clomiphene citrate group, pregnancy rate in metformin group was significantly lower [Peto OR = 1.56 (1.16–2.08), p = 0.003], but there was no significant difference in the two groups about ovulation rate [OR = 1.52 (0.95–2.45)], miscarriage rate [Peto OR = 1.40 (0.79–2.48)]. Conclusions: Compared with clomiphene citrate, metformin used for ovulation induction treatment in PCOS women, can promote ovulation induction and pregnancy rate, the effect of the combination treatment is better than that of a single drug use.     

二甲双胍用于多囊卵巢综合征患者促排卵治疗有效性的系统性评价

目的:系统性评价二甲双胍对多囊卵巢综合征(PCOS)促排卵治疗的有效性。方法:计算机检索CBMDISC(中国生物医学文献数据库,1979～2011年)、万方(1994～2011年)、CNKI(中国学术期刊网专题全文数据库,1994～2011年)、维普(中国生物医学期刊数据库,1989～2011年),PubMed(1997～2011年)、ProQust Medical Libraray(PML,1997～2011年)、外文生物医学期刊文献数据库(FMJS,2000～2011年),读秀学术搜索(www.duxiu.com),并手检9种相关杂志。纳入二甲双胍与氯米芬用于PCOS促排卵治疗的随机对照试验,质量评价后进行Meta分析。结果:共纳入8篇RCT,合计1168例。Meta分析结果显示:与氯米芬组比较,二甲双胍组排卵率低于氯米芬组[OR 0.48(0.26～0.87)],两组差异有统计学意义;妊娠率[OR 0.94(0.26～3.43)],流产率[OR 0.63(0.06～6.47)],活产率[OR 0.90(0.11～7.32)],两组差异无统计学意义。氯米芬联合二甲双胍组妊娠率较高,与氯米芬组的差异有统计学意义[Peto OR 1.56(1.16～2.08)];排卵率[OR 1.54(0.96～2.49)],流产率[Peto OR 1.40(0.79～2.48)],活产率[Peto OR1.26(0.83～1.91)],两组差异无统计学意义。结论:较之氯米芬用于PCOS患者促排卵治疗,二甲双胍可能促进排卵、有利于妊娠,二甲双胍与氯米芬联合用药的治疗效果要好于单一用药。     

Evaluating the equivalence of clomiphene citrate with and without metformin in ovulation induction in PCOS patients

Objective  To evaluate the benefit of Metfomin added to Clomiphene Citrate in a primary ovulation induction protocol in PCOS patients Design  Prospective randomised controlled study Setting  Tygerberg Academic Hospital, Stellenbosch University and the Institute of Reproductive Medicine at Vincent Pallotti Hospital, Cape Town Patients  107 patients presenting with PCOS Study  Group A was pre-treated with metformin 850 mg twice a day for at least 6 weeks before clomiphene was added and the metformin was used throughout the study period. Group B received clomiphene without pre-treatment with metformin. In both groups clomiphene was given at a starting dose of 50 mg day 4–8 and increase with increments of 50 mg to a maximum of 150 mg if no response was achieved. Results  The ovulation rate achieved in women in the M+C/C arm was 34/52 (65.4%) compared to 36/55 (65.5%) in the C/C arm. The treatment effect ((M+C/C) – C/C) is 0% with 95% confidence interval of −18.1% to 18%. The per protocol ovulation results were 34/42 (81%) in the M+C/C arm compared to 36/48 (75%) in the C/C arm. The ovulation rate difference was 6% with 95% confidence interval −11% to 22%. In a comparison of successful ovulating versus non-ovulating women from the trial the following were significant baseline determinants: lower median weight in the ovulating group (77 kg versus 86 kg, p = .021), lower median bmi (29.0 versus 32.9, p = .009), lower median DHEAS at baseline (4.6 compared to 7.0, p = .049), lower median 17OH-progesterone (2.2 versus 4.6, p = .027) and higher baseline median SHBG ( 37.8 compared to 28.5, p = .036). Conclusion  Although identical ovulation rates were observed in both arms equivalence could not be concluded with respect to the specified criteria. Capsule   Clomiphene with Metformin achieved the same ovulation rate (65%) compared to Clomiphene alone. However the 2-sided 95% confidence interval for ovulation rate difference was −18.1% to 18%.     

Short-term effects of metformin and myo-inositol in women with polycystic ovarian syndrome (PCOS): a meta-analysis of randomized clinical trials

Metformin (MET), the most commonly used insulin sensitizer, is the reference off-label drug for the treatment of polycystic ovary syndrome (PCOS), worldwide. However, its use may be limited mainly by gastrointestinal adverse effects. Myo-inositol (MI), a well-recognized food supplement, also represents an evidence-based treatment for PCOS women, popular in many countries. Our aim is to provide a systematic review of the literature and a meta-analysis which compares these two treatments, for their short-term efficacy and safety in PCOS patients. Systematic review and meta-analysis of randomized clinical trials (RCTs). RCTs were identified from 1994 through 2017 using MEDLINE, Cochrane Library, PubMed, and ResearchGate. Included studies were limited to those one directly comparing MET to MI on several hormones changes. Standardized mean difference (SMD) or risk ratios (RRs) with 95% CIs were calculated. Changes in fasting insulin was the main outcome of measure. Six trials with a total of 355 patients were included. At the end of treatment, no difference between MET and MI was found on fasting insulin (SMD=0.08 µU/ml, 95% CI: ?0.31–0.46, p=.697), HOMA index (SMD =0.17, 95% CI: ?0.53–0.88, p=.635), testosterone (SMD=??0.01, 95% CI: ?0.24–0.21, p=.922), SHBG levels (SMD=??0.50?nmol/l, 95% CI: ?1.39–0.38, p=.263) and body mass index (BMI) (SMD=??0.22, 95% CI: ?0.60–0.16, p=.265). There was strong evidence of an increased risk of adverse events among women receiving MET compared to those receiving MI (RR =5.17, 95% CI: 2.91–9.17, p<.001). No differences were found in the effect of MET and MI on short-term hormone changes. The better tolerability of MI makes it more acceptable for the recovery of androgenic and metabolic profile in PCOS women.     

Clomiphene Citrate co-treatment with low dose urinary FSH versus urinary FSH for clomiphene resistant PCOS: randomized controlled trial

Purpose

The aim of this study was to examine the effect of clomiphene citrate [CC] co-administration during the use of exogenous low-dose urinary FSH [uFSH] for induction of ovulation in CC-resistant infertile PCOS women.

Methods

In a randomised controlled setting, 174 CC-resistant infertile PCOS women were randomized into two parallel groups; Group I received CC 100 mg/day for 5 days plus uFSH 37.5 IU/day while group II received only uFSH 37.5 IU /day. Subsequent increments of uFSH by 37.5 IU/day were made according to response. Primary outcome was ovulation rate. Secondary outcomes were clinical pregnancy rates, number of follicles, endometrial thickness, and gonadotropins consumption.

Results

Our results have demonstrated that group I compared to group II had significantly higher ovulation rate per intention to treat [ITT] [72.4 % vs. 34.2 %, p < 0.001]. Clinical pregnancy and live birth rates were comparable between the two groups. Group I consumed significantly lower total FSH dose and needed significantly shorter stimulation duration compared to group II.

Conclusion

CC co-administered during low dose HP uFSH versus uFSH for CC-resistant PCOS yields significantly higher ovulation rate and less consumption of FSH.     

Response to ovulation induction treatments in women with polycystic ovary syndrome as a function of serum anti-Müllerian hormone levels

PurposeTo assess whether anti-Müllerian hormone (AMH) can predict response to ovulation induction (OI) with clomiphene citrate (CC), letrozole (LET), or follicle-stimulating hormone (FSH) in women with polycystic ovary syndrome (PCOS) undergoing OI/intrauterine inseminations (IUI).MethodsA total of 738 OI/IUI cycles from 242 patients at an academic center were stratified in three groups by medication: CC (n = 295), LET (n = 180), and FSH (n = 263), in a retrospective fashion. Ovarian response to treatment (RT, development of at least one dominant follicle) was assessed using mixed effects logistic regression models.ResultsOverall, RT cycles had lower AMH levels compared to no-RT cycles (p < 0.001). This finding persisted when analysis was limited to oral agents but attenuated in FSH cycles. For CC and LET cycles, the predicted probability (PProb) for RT decreased as AMH levels increased (PProb (95%CI): 97% (93–100), 79% (70–88), and 75% (61–89); 85% (78–93), 75% (67–83), and 73% (63–86) for AMH pct.: ≤ 25th, ≥ 50th, and ≥ 75th, for CC and LET, respectively)). However, RT was noted in 98.5% of FSH/IUI cycles regardless of AMH. For CC cycles, those with AMH ≥ 75th pct. had lower odds for RT over cycles with AMH < 75th pct. (OR 0.2, 95%CI 0.04–0.8, p = 0.02). Similarly, lower odds for RT were observed in LET cycles with AMH ≥ 75th pct. (0.6, 0.3–1.4, p = 0.25).ConclusionIn PCOS, increasing serum AMH levels are associated with lower probability of RT to oral agents. Our findings constitute a valuable tool for the clinician when counseling PCOS patients and designing a personalized ovulation induction treatment strategy.     

Effects of metformin on adrenal steroidogenesis in women with polycystic ovary syndrome

Objective: To determine whether the administration of metformin, an insulin-sensitizing agent, is followed by changes in adrenal steroidogenesis in women with polycystic ovary syndrome (PCOS).

Design: Prospective trial.

Setting: Department of Obstetrics and Gynecology, University of Siena, Siena, Italy.

Patient(s): Fourteen women with PCOS.

Intervention(s): Blood samples were obtained before (−15 and 0 minutes) and after (15, 30, 45, and 60 minutes) the administration of ACTH (250 μg). Metformin then was given at a dosage of 500 mg three times a day for 30–32 days, at which time the pretreatment study was repeated.

Main Outcome Measure(s): The adrenal androgen responses to ACTH before and after treatment with metformin.

Result(s): Ovulation occurred in two women (14%) in response to metformin treatment. A significant reduction in basal concentrations of free testosterone and a significant increase in concentrations of sex hormone-binding globulin were observed. The administration of metformin was associated with a significant reduction in the response of 17-hydroxyprogesterone, testosterone, free testosterone, and androstenedione to ACTH. The ratio of 17-hydroxyprogesterone to progesterone, which indicates 17-hydroxylase activity, and the ratio of androstenedione to 17-hydroxyprogesterone, which indicates 17,20-lyase activity, were significantly lower after a month of metformin treatment, indicating a reduction in the activities of these enzymes.

Conclusion(s): The administration of metformin to unselected women with PCOS led to a reduction in the adrenal steroidogenesis response to ACTH. This finding supports the hypothesis that high insulin levels associated with PCOS may cause an increase in plasma levels of adrenal androgens.     

腹腔镜卵巢打孔术结合药物促排卵治疗难治性多囊卵巢综合征的临床研究

目的　探讨腹腔镜卵巢打孔术 (LOD)后结合克罗米芬 (CC)和中药排卵汤对难治性多囊卵巢综合征(PCOS)不孕的治疗效果。方法　 1998年 2月至 2 0 0 3年 4月将 5 8例患者随机分成A组 (LOD) 18例 ,B组(LOD CC) 2 1例及C组 (LOD CC 排卵汤 ) 19例 ,所有患者进行LOD。手术前后分别测血黄体生成激素、卵泡刺激素、雄激素及雌二醇水平 ,术后第 9天起监测患者卵泡发育和排卵共 3个周期 ,并记录妊娠数和流产数。结果　三组患者术后LH和T水平与术前相比均有显著性下降 (P <0 0 1)。 3个治疗周期内共有 4 5例排卵 ,其中A组 9例 (5 0 0 % ) ,B组 19例 (90 5 % ) ,C组 17例 (89 5 % ) ,三组间排卵率差异有显著性意义 (P <0 0 0 5 )。1年内累计妊娠 2 6例 ,其中A组 3例 ,B组 10例 ,C组 13例。自然流产A组有 1例 ,B组 2例 ,C组无发生。结论　LOD后结合CC和中药排卵汤能明显改善难治性PCOS患者的排卵和受孕机会。     

多囊卵巢综合征促排卵失败的相关因素探讨

探讨多囊卵巢综合征（ＰＣＯＳ）妇女促排卵失败的危险因素。方法：将 １０３名ＰＣＯＳ病人,随机分为 ３组,分别以 ＣＣ／ ｈＣＧ、ＣＣ／ｈＭＧ／ｈＣＧ及 ＧｎＲＨ－ａ／ｈＭＧ／ｈＣＧ三种促排卵方案治疗,并以 ３１名正常妇女作对照,应用放免法测定４组对象血清性激素水平。应用糖耐量试验及胰岛素释放试验测定糖负荷后 ０ ｍｉｎ、 ６０ ｍｉｎ、 １２０ ｍｉｎ血糖及胰岛素水平。结果：促排卵治疗失败者卵巢过度刺激综合征（ＯＧＴＴ）后 １２０ ｍｉｎ胰岛素水平明显增高,与排卵者相比,Ｐ＜０．０５,ＯＲ＝１．０１３;而 ＣＣ／ｈＭＧ／ｈＣＧ治疗方案失败率较低,ＯＲ＝０． ３１１０。结论：ＯＧＴＴ后 １２０ ｍｉｎ胰岛素是促排卵失败的危险因素, ＣＣ／ｈＭＧ／ｈＣＧ方案是较为成功的促排卵治疗方案。