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The Cochrane Database of Systematic... Feb 2020Polycystic ovary syndrome (PCOS) is a common condition affecting 8% to 13% of reproductive-aged women. In the past clomiphene citrate (CC) used to be the first-line... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Polycystic ovary syndrome (PCOS) is a common condition affecting 8% to 13% of reproductive-aged women. In the past clomiphene citrate (CC) used to be the first-line treatment in women with PCOS. Ovulation induction with letrozole should be the first-line treatment according to new guidelines, but the use of letrozole is off-label. Consequently, CC is still commonly used. Approximately 20% of women on CC do not ovulate. Women who are CC-resistant can be treated with gonadotrophins or other medical ovulation-induction agents. These medications are not always successful, can be time-consuming and can cause adverse events like multiple pregnancies and cycle cancellation due to an excessive response. Laparoscopic ovarian drilling (LOD) is a surgical alternative to medical treatment. There are risks associated with surgery, such as complications from anaesthesia, infection, and adhesions.
OBJECTIVES
To evaluate the effectiveness and safety of LOD with or without medical ovulation induction compared with medical ovulation induction alone for women with anovulatory polycystic PCOS and CC-resistance.
SEARCH METHODS
We searched the Cochrane Gynaecology and Fertility Group (CGFG) trials register, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL and two trials registers up to 8 October 2019, together with reference checking and contact with study authors and experts in the field to identify additional studies.
SELECTION CRITERIA
We included randomised controlled trials (RCTs) of women with anovulatory PCOS and CC resistance who underwent LOD with or without medical ovulation induction versus medical ovulation induction alone, LOD with assisted reproductive technologies (ART) versus ART, LOD with second-look laparoscopy versus expectant management, or different techniques of LOD.
DATA COLLECTION AND ANALYSIS
Two review authors independently selected studies, assessed risks of bias, extracted data and evaluated the quality of the evidence using the GRADE method. The primary effectiveness outcome was live birth and the primary safety outcome was multiple pregnancy. Pregnancy, miscarriage, ovarian hyperstimulation syndrome (OHSS), ovulation, costs, and quality of life were secondary outcomes.
MAIN RESULTS
This updated review includes 38 trials (3326 women). The evidence was very low- to moderate-quality; the main limitations were due to poor reporting of study methods, with downgrading for risks of bias (randomisation and allocation concealment) and lack of blinding. Laparoscopic ovarian drilling with or without medical ovulation induction versus medical ovulation induction alone Pooled results suggest LOD may decrease live birth slightly when compared with medical ovulation induction alone (odds ratio (OR) 0.71, 95% confidence interval (CI) 0.54 to 0.92; 9 studies, 1015 women; I = 0%; low-quality evidence). The evidence suggest that if the chance of live birth following medical ovulation induction alone is 42%, the chance following LOD would be between 28% and 40%. The sensitivity analysis restricted to only RCTs with low risk of selection bias suggested there is uncertainty whether there is a difference between the treatments (OR 0.90, 95% CI 0.59 to 1.36; 4 studies, 415 women; I = 0%, low-quality evidence). LOD probably reduces multiple pregnancy rates (Peto OR 0.34, 95% CI 0.18 to 0.66; 14 studies, 1161 women; I = 2%; moderate-quality evidence). This suggests that if we assume the risk of multiple pregnancy following medical ovulation induction is 5.0%, the risk following LOD would be between 0.9% and 3.4%. Restricting to RCTs that followed women for six months after LOD and six cycles of ovulation induction only, the results for live birth were consistent with the main analysis. There may be little or no difference between the treatments for the likelihood of a clinical pregnancy (OR 0.86, 95% CI 0.72 to 1.03; 21 studies, 2016 women; I = 19%; low-quality evidence). There is uncertainty about the effect of LOD compared with ovulation induction alone on miscarriage (OR 1.11, 95% CI 0.78 to 1.59; 19 studies, 1909 women; I = 0%; low-quality evidence). OHSS was a very rare event. LOD may reduce OHSS (Peto OR 0.25, 95% CI 0.07 to 0.91; 8 studies, 722 women; I = 0%; low-quality evidence). Unilateral LOD versus bilateral LOD Due to the small sample size, the quality of evidence is insufficient to justify a conclusion on live birth (OR 0.83, 95% CI 0.24 to 2.78; 1 study, 44 women; very low-quality evidence). There were no data available on multiple pregnancy. The likelihood of a clinical pregnancy is uncertain between the treatments, due to the quality of the evidence and the large heterogeneity between the studies (OR 0.57, 95% CI 0.39 to 0.84; 7 studies, 470 women; I = 60%, very low-quality evidence). Due to the small sample size, the quality of evidence is not sufficient to justify a conclusion on miscarriage (OR 1.02, 95% CI 0.31 to 3.33; 2 studies, 131 women; I = 0%; very low-quality evidence). Other comparisons Due to lack of evidence and very low-quality data there is uncertainty whether there is a difference for any of the following comparisons: LOD with IVF versus IVF, LOD with second-look laparoscopy versus expectant management, monopolar versus bipolar LOD, and adjusted thermal dose versus fixed thermal dose.
AUTHORS' CONCLUSIONS
Laparoscopic ovarian drilling with and without medical ovulation induction may decrease the live birth rate in women with anovulatory PCOS and CC resistance compared with medical ovulation induction alone. But the sensitivity analysis restricted to only RCTs at low risk of selection bias suggests there is uncertainty whether there is a difference between the treatments, due to uncertainty around the estimate. Moderate-quality evidence shows that LOD probably reduces the number of multiple pregnancy. Low-quality evidence suggests that there may be little or no difference between the treatments for the likelihood of a clinical pregnancy, and there is uncertainty about the effect of LOD compared with ovulation induction alone on miscarriage. LOD may result in less OHSS. The quality of evidence is insufficient to justify a conclusion on live birth, clinical pregnancy or miscarriage rate for the analysis of unilateral LOD versus bilateral LOD. There were no data available on multiple pregnancy.
Topics: Anovulation; Birth Rate; Female; Fertility Agents, Female; Humans; Infertility, Female; Laparoscopy; Ovulation Induction; Polycystic Ovary Syndrome; Pregnancy; Pregnancy Rate; Randomized Controlled Trials as Topic
PubMed: 32048270
DOI: 10.1002/14651858.CD001122.pub5 -
The Cochrane Database of Systematic... Dec 2019Polycystic ovary syndrome (PCOS) is characterised by infrequent or absent ovulation, and high levels of androgens and insulin (hyperinsulinaemia). Hyperinsulinaemia... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Polycystic ovary syndrome (PCOS) is characterised by infrequent or absent ovulation, and high levels of androgens and insulin (hyperinsulinaemia). Hyperinsulinaemia occurs secondary to insulin resistance and is associated with an increased biochemical risk profile for cardiovascular disease and an increased prevalence of diabetes mellitus. Insulin-sensitising agents such as metformin may be effective in treating PCOS-related anovulation. This is an update of Morley 2017 and only includes studies on metformin.
OBJECTIVES
To evaluate the effectiveness and safety of metformin in combination with or in comparison to clomiphene citrate (CC), letrozole and laparoscopic ovarian drilling (LOD) in improving reproductive outcomes and associated gastrointestinal side effects for women with PCOS undergoing ovulation induction.
SEARCH METHODS
We searched the following databases from inception to December 2018: Cochrane Gynaecology and Fertility Group Specialised Register, CENTRAL, MEDLINE, Embase, PsycINFO and CINAHL. We searched registers of ongoing trials and reference lists from relevant studies.
SELECTION CRITERIA
We included randomised controlled trials of metformin compared with placebo, no treatment, or in combination with or compared with CC, letrozole and LOD for women with PCOS subfertility.
DATA COLLECTION AND ANALYSIS
Two review authors independently assessed studies for eligibility and bias. Primary outcomes were live birth rate and gastrointestinal adverse effects. Secondary outcomes included other pregnancy outcomes and ovulation. We combined data to calculate pooled odds ratios (ORs) and 95% confidence intervals (CIs). We assessed statistical heterogeneity using the I statistic and reported quality of the evidence for primary outcomes and reproductive outcomes using GRADE methodology.
MAIN RESULTS
We included 41 studies (4552 women). Evidence quality ranged from very low to moderate based on GRADE assessment. Limitations were risk of bias (poor reporting of methodology and incomplete outcome data), imprecision and inconsistency. Metformin versus placebo or no treatment The evidence suggests that metformin may improve live birth rates compared with placebo (OR 1.59, 95% CI 1.00 to 2.51; I = 0%; 4 studies, 435 women; low-quality evidence). For a live birth rate of 19% following placebo, the live birth rate following metformin would be between 19% and 37%. The metformin group probably experiences more gastrointestinal side effects (OR 4.00, 95% CI 2.63 to 6.09; I = 39%; 7 studies, 713 women; moderate-quality evidence). With placebo, the risk of gastrointestinal side effects is 10% whereas with metformin this risk is between 22% and 40%. There are probably higher rates of clinical pregnancy (OR 1.98, 95% CI 1.47 to 2.65; I = 30%; 11 studies, 1213 women; moderate-quality evidence). There may be higher rates of ovulation with metformin (OR 2.64, 95% CI 1.85 to 3.75; I = 61%; 13 studies, 684 women; low-quality evidence). We are uncertain about the effect on miscarriage rates (OR 1.08, 95% CI 0.50 to 2.35; I = 0%; 4 studies, 748 women; low-quality evidence). Metformin plus CC versus CC alone We are uncertain if metformin plus CC improves live birth rates compared to CC alone (OR 1.27, 95% CI 0.98 to 1.65; I = 28%; 10 studies, 1219 women; low-quality evidence), but gastrointestinal side effects are probably more common with combined therapy (OR 4.26, 95% CI 2.83 to 6.40; I = 8%; 6 studies, 852 women; moderate quality evidence). The live birth rate with CC alone is 24%, which may change to between 23% to 34% with combined therapy. With CC alone, the risk of gastrointestinal side effects is 9%, which increases to between 21% to 37% with combined therapy. The combined therapy group probably has higher rates of clinical pregnancy (OR 1.62, 95% CI 1.32 to 1.99; I = 31%; 19 studies, 1790 women; moderate-quality evidence). The combined group may have higher rates of ovulation (OR 1.65, 95% CI 1.35 to 2.03; I = 63%;21 studies, 1568 women; low-quality evidence). There was no clear evidence of an effect on miscarriage (OR 1.35, 95% CI 0.91 to 2.00; I = 0%; 10 studies, 1206 women; low-quality evidence). Metformin versus CC When all studies were combined, findings for live birth were inconclusive and inconsistent (OR 0.71, 95% CI 0.49 to 1.01; I = 86%; 5 studies, 741 women; very low-quality evidence). In subgroup analysis by obesity status, obese women had a lower birth rate in the metformin group (OR 0.30, 95% CI 0.17 to 0.52; 2 studies, 500 women), while the non-obese group showed a possible benefit from metformin, with high heterogeneity (OR 1.71, 95% CI 1.00 to 2.94; I = 78%, 3 studies, 241 women; very low-quality evidence). However, due to the very low quality of the evidence we cannot draw any conclusions. Among obese women taking metformin there may be lower rates of clinical pregnancy (OR 0.34, 95% CI 0.21 to 0.55; I = 0%; 2 studies, 500 women; low-quality evidence) and ovulation (OR 0.29, 95% CI 0.20 to 0.43; I = 0%; 2 studies, 500 women; low-quality evidence) while among non-obese women, the metformin group may have more pregnancies (OR 1.56, 95% CI 1.06 to 2.29; I = 26%; 6 studies, 530 women; low-quality evidence) and no clear difference in ovulation rates (OR 0.80, 95% CI 0.52 to 1.25; I = 0%; 5 studies, 352 women; low-quality evidence). We are uncertain whether there is a difference in miscarriage rates between the groups (overall: OR 0.92, 95% CI 0.51 to 1.66; I = 36%; 6 studies, 781 women; low-quality evidence) and no studies reported gastrointestinal side effects.
AUTHORS' CONCLUSIONS
Our updated review suggests that metformin may be beneficial over placebo for live birth however, more women probably experience gastrointestinal side effects. We are uncertain if metformin plus CC improves live birth rates compared to CC alone, but gastrointestinal side effects are probably increased with combined therapy. When metformin was compared with CC, data for live birth were inconclusive, and the findings were limited by lack of evidence. Results differed by body mass index (BMI), emphasising the importance of stratifying results by BMI. No studies reported gastrointestinal side effects in this comparison. Due to the low quality of the evidence, we are uncertain of the effect of metformin on miscarriage in all three comparisons.
Topics: Abortion, Spontaneous; Birth Rate; Body Mass Index; Clomiphene; Female; Fertility Agents, Female; Humans; Infertility, Female; Metformin; Ovary; Ovulation Induction; Polycystic Ovary Syndrome; Pregnancy; Pregnancy Outcome; Pregnancy Rate; Randomized Controlled Trials as Topic
PubMed: 31845767
DOI: 10.1002/14651858.CD013505 -
Frontiers in Endocrinology 2019Twenty-one-hydroxylase-deficient non-classic adrenal hyperplasia (NC-CAH) is a very common autosomal recessive syndrome with prevalence between 1:1,000 and 1:2,000...
Twenty-one-hydroxylase-deficient non-classic adrenal hyperplasia (NC-CAH) is a very common autosomal recessive syndrome with prevalence between 1:1,000 and 1:2,000 individuals and the frequency varies according to ethnicity. On the other hand, polycystic ovary syndrome has a familial basis and it is inherited under a complex hereditary trait. This syndrome affects 6 to 10% of women in reproductive age and it is the most common endocrine disorder in young women. Our aim was to investigate, through a systematic review, the distinct characteristics and common findings of these syndromes. The search period covered January 1970 to November 2018, using the scientific databases PubMed. Inclusion criteria were adult women patients with PCOS or NC-CAH. Search terms were "polycystic ovary syndrome," "PCOS," "non-classical adrenal hyperplasia," "NC-CAH," "21-hydroxylase deficiency." From an initial 16,255 titles, the evaluations led to the final inclusion of 97 papers. The clinical features of NC-CAH are hirsutism and ovulatory and menstrual dysfunction therefore; differentiation between these two syndromes is difficult based on clinical grounds only. Additionally, NC-CAH and PCOS are both associated with obesity, insulin resistance, and dyslipidaemia. Reproductive abnormalities are also common between these hyperandrogenemic disorders since in patients with NC-CAH polycystic ovarian morphology and subfertility are present as they are in women with PCOS. The diagnosis of PCOS, is confirmed once other disorders that mimic PCOS have been excluded e.g., conditions that are related to oligoovulation or anovulation and/or hyperandrogenism, such as hyperprolactinaemia, thyroid disorders, non-classic congenital adrenal hyperplasia, and androgen-producing neoplasms. The screening tool to distinguish non-classic adrenal hyperplasia from PCOS is the measurement of 17-hydroxyprogesterone levels. The basal levels of 17-hydroxyprogesterone may overlap, but ACTH stimulation testing can distinguish the two entities. In this review these two common endocrine disorders are discussed in an effort to unveil their commonalities and to illuminate their shadowed distinctive characteristics.
PubMed: 31275245
DOI: 10.3389/fendo.2019.00388 -
The Cochrane Database of Systematic... Nov 2017Polycystic ovary syndrome (PCOS) is characterised by infrequent or absent ovulation, and high levels of androgens and insulin (hyperinsulinaemia). Hyperinsulinaemia... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Polycystic ovary syndrome (PCOS) is characterised by infrequent or absent ovulation, and high levels of androgens and insulin (hyperinsulinaemia). Hyperinsulinaemia occurs secondary to insulin resistance and is associated with increased risk of cardiovascular disease and diabetes mellitus. Insulin-sensitising agents such as metformin may be effective in treating PCOS-related anovulation.
OBJECTIVES
To evaluate the effectiveness and safety of insulin-sensitising drugs in improving reproductive and metabolic outcomes for women with PCOS undergoing ovulation induction.
SEARCH METHODS
We searched the following databases from inception to January 2017: Cochrane Gynaecology and Fertility Group Specialised Register, CENTRAL, MEDLINE, Embase, PsycINFO and CINAHL. We searched registers of ongoing trials and reference lists from relevant studies.
SELECTION CRITERIA
We included randomised controlled trials of insulin-sensitising drugs compared with placebo, no treatment, or an ovulation-induction agent for women with oligo and anovulatory PCOS.
DATA COLLECTION AND ANALYSIS
Two review authors independently assessed studies for eligibility and bias. Primary outcomes were live birth rate and gastrointestinal adverse effects. Secondary outcomes included other pregnancy outcomes, menstrual frequency and metabolic effects. We combined data to calculate pooled odds ratios (ORs) and 95% confidence intervals (CIs). We assessed statistical heterogeneity using the I statistic and reported quality of the evidence for primary outcomes using GRADE methodology.
MAIN RESULTS
We assessed the interventions metformin, clomiphene citrate, metformin plus clomiphene citrate, D-chiro-inositol, rosiglitazone and pioglitazone. We compared these with each other, placebo or no treatment. We included 48 studies (4451 women), 42 of which investigated metformin (4024 women). Evidence quality ranged from very low to moderate. Limitations were risk of bias (poor reporting of methodology and incomplete outcome data), imprecision and inconsistency. Metformin versus placebo or no treatmentThe evidence suggests that metformin may improve live birth rates compared with placebo (OR 1.59, 95% CI 1.00 to 2.51, 4 studies, 435 women, I = 0%, low-quality evidence). The metformin group experienced more gastrointestinal side effects (OR 4.76, 95% CI 3.06 to 7.41, 7 studies, 670 women, I = 61%, moderate-quality evidence) but had higher rates of clinical pregnancy (OR 1.93, 95% CI 1.42 to 2.64, 9 studies, 1027 women, I = 43%, moderate-quality evidence), ovulation (OR 2.55, 95% CI 1.81 to 3.59, 14 studies, 701 women, I = 58%, moderate-quality evidence) and menstrual frequency (OR 1.72, 95% CI 1.14 to 2.61, 7 studies, 427 women, I = 54%, low-quality evidence). There was no clear evidence of a difference in miscarriage rates (OR 1.08, 95% CI 0.50 to 2.35, 4 studies, 748 women, I = 0%, low-quality evidence). Metformin plus clomiphene citrate versus clomiphene citrate alone There was no conclusive evidence of a difference between the groups in live birth rates (OR 1.21, 95% CI 0.92 to 1.59, 9 studies, 1079 women, I = 20%, low-quality evidence), but gastrointestinal side effects were more common with combined therapy (OR 3.97, 95% CI 2.59 to 6.08, 3 studies, 591 women, I = 47%, moderate-quality evidence). However, the combined therapy group had higher rates of clinical pregnancy (OR 1.59, 95% CI 1.27 to 1.99, 16 studies, 1529 women, I = 33%, moderate-quality evidence) and ovulation (OR 1.57, 95% CI 1.28 to 1.92, 21 studies, 1624 women, I = 64%, moderate-quality evidence). There was a statistically significant difference in miscarriage rate per woman, with higher rates in the combined therapy group (OR 1.59, 95% CI 1.03 to 2.46, 9 studies, 1096 women, I = 0%, low-quality evidence) but this is of uncertain clinical significance due to low-quality evidence, and no clear difference between groups when we analysed miscarriage per pregnancy (OR 1.30, 95% CI 0.80 to 2.12, 8 studies; 400 pregnancies, I = 0%, low-quality evidence). Metformin versus clomiphene citrateWhen all studies were combined, findings for live birth were inconclusive and inconsistent (OR 0.71, 95% CI 0.49 to 1.01, 5 studies, 741 women, I = 86%, very low-quality evidence). In subgroup analysis by obesity status, obese women had a lower birth rate in the metformin group (OR 0.30, 95% CI 0.17 to 0.52, 2 studies, 500 women, I = 0%, very low-quality evidence), while data from the non-obese group showed a possible benefit from metformin, with high heterogeneity (OR 1.71, 95% CI 1.00 to 2.94, 3 studies, 241 women, I = 78%, very low-quality evidence). Similarly, among obese women taking metformin there were lower rates of clinical pregnancy (OR 0.34, 95% CI 0.21 to 0.55, 2 studies, 500 women, I = 0%, very low-quality evidence) and ovulation (OR 0.29, 95% CI 0.20 to 0.43 2 studies, 500 women, I = 0%, low-quality evidence) while among non-obese women, the metformin group had more pregnancies (OR 1.56, 95% CI 1.05 to 2.33, 5 studies, 490 women, I = 41%, very low-quality evidence) and no clear difference in ovulation rates (OR 0.81, 95% CI 0.51 to 1.28, 4 studies, 312 women, low-quality evidence, I=0%). There was no clear evidence of a difference in miscarriage rates (overall: OR 0.92, 95% CI 0.50 to 1.67, 5 studies, 741 women, I = 52%, very low-quality evidence). D-chiro-inositol (2 studies), rosiglitazone (1 study) or pioglitazone (1 study) versus placebo or no treatmentWe were unable to draw conclusions regarding other insulin-sensitising drugs as no studies reported primary outcomes.
AUTHORS' CONCLUSIONS
Our updated review suggests that metformin alone may be beneficial over placebo for live birth, although the evidence quality was low. When metformin was compared with clomiphene citrate, data for live birth were inconclusive, and our findings were limited by lack of evidence. Results differed by body mass index (BMI), emphasising the importance of stratifying results by BMI. An improvement in clinical pregnancy and ovulation suggests that clomiphene citrate remains preferable to metformin for ovulation induction in obese women with PCOS.An improved clinical pregnancy and ovulation rate with metformin and clomiphene citrate versus clomiphene citrate alone suggests that combined therapy may be useful although we do not know whether this translates into increased live births. Women taking metformin alone or with combined therapy should be advised that there is no evidence of increased miscarriages, but gastrointestinal side effects are more likely.
Topics: Abortion, Spontaneous; Anovulation; Clomiphene; Female; Humans; Hypoglycemic Agents; Infertility, Female; Inositol; Insulin Resistance; Live Birth; Metformin; Ovulation Induction; Pioglitazone; Polycystic Ovary Syndrome; Pregnancy; Pregnancy Rate; Randomized Controlled Trials as Topic; Rosiglitazone; Thiazolidinediones
PubMed: 29183107
DOI: 10.1002/14651858.CD003053.pub6 -
The Cochrane Database of Systematic... Nov 2017Polycystic ovary syndrome (PCOS) is a common endocrine condition, affecting approximately one in 10 women. PCOS is defined by two of three features: oligo- or... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Polycystic ovary syndrome (PCOS) is a common endocrine condition, affecting approximately one in 10 women. PCOS is defined by two of three features: oligo- or anovulation, clinical or biochemical hyperandrogenism or both, or polycystic ovaries.Women with PCOS can have a wide range of health problems, including infrequent and irregular periods, unwanted hair growth and acne, and subnormal fertility. Long-term health concerns include an increased risk of heart disease, diabetes and the development of precancerous disease of the womb.
OBJECTIVES
To assess the effectiveness and harms of ovarian surgery as a treatment for symptomatic relief of hirsutism, acne and menstrual irregularity in PCOS.
SEARCH METHODS
We searched the Cochrane Gynaecology and Fertility Group specialized register, CENTRAL, MEDLINE, Embase and PsycINFO (from inception to 17 October 2016). We handsearched citation lists, registers of ongoing trials and conference proceedings.
SELECTION CRITERIA
We included randomized controlled trials (RCTs) of women undergoing ovarian drilling in comparison to no treatment, medical treatment, or other forms of surgical treatment for the symptoms of PCOS.
DATA COLLECTION AND ANALYSIS
We used standard methodological procedures recommended by Cochrane. The primary outcome measures were improvement in menstrual regularity and androgenic symptoms of PCOS (hirsutism, acne); the secondary outcome measures included harms, change of body mass index (BMI), waist circumference, androgen levels, metabolic measures and quality of life. We assessed the quality of the evidence using GRADE methods.
MAIN RESULTS
We included 22 RCTs (2278 women analyzed) of participants with PCOS and symptoms of acne, hirsutism or irregular menstrual cycles, all of which included laparoscopic ovarian drilling (LOD) as an intervention.Two studies reported their funding source (Farquhar 2002 - supported in part by the Auckland Medical Research Foundation; Sarouri 2015 - the authors thank the Vice Chancellor for Research of Guilan University of Medical Sciences for funding this project).The quality of the evidence ranged from very low to moderate quality. The main limitations were imprecision associated with the low number of studies, inconsistency and risk of bias associated with the inability to blind participants. There were too few studies to assess risk of publication bias. Menstrual RegularityTwo studies compared LOD versus metformin (n=226) but no conclusions could be drawn with regard to menstrual regularity, as their findings were inconsistent and they were unsuitable for pooling. There appeared to be little or no difference in the rate of women reporting improvement in menstrual regularity when LOD was compared with medical treatment including metformin + clomiphene (OR 1.02, 95% CI 0.64 to 1.64, 2 studies, 332 women, I = 13%, low-quality evidence), letrozole (OR 1.08, 95% CI 0.64 to 1.84, 1 study, 260 women, low-quality evidence), or metformin + letrozole (OR 0.95, 95% CI 0.49 to 1.81, 1 study, 146 women, low-quality evidence). However, one study reported that LOD was superior to gonadotrophin (OR 19.2, 95% CI 3.17 to 116.45, 1 study, 35 women, very low-quality evidence).There appeared to be little or no difference in the rate of women reporting improvement in menstrual regularity when bilateral unipolar LOD was compared to unilateral LOD (OR 1.51, 95% CI 0.62 to 3.71, 2 studies, 104 women, I = 0%, moderate-quality evidence), transvaginal ultrasound-guided LOD (OR 1.23, 95% CI 0.64 to 2.37, 1 study, 147 women, low-quality evidence), LOD using adjusted thermal dose in accordance with the ovarian volume (OR 0.42, 95% CI 0.16 to 1.14, 1 study, 115 women, low-quality evidence) or bipolar LOD (OR 1.00, 95% CI 0.05 to 18.57, 1 study, 18 women, low-quality evidence).Four to five punctures per ovary may improve the rate of women reporting menstrual regularity compared with two or fewer (OR 16.04, 95% CI 4.19 to 61.34, 2 studies, 73 women, I = 0%, low-quality evidence). Androgenic SymptomsThere was probably little or no difference in improvement in androgenic symptoms when LOD was compared to metformin (OR 1.00, 95% CI 0.42 to 2.37, 1 study, 126 women, moderate-quality evidence) or gonadotrophins; acne (OR 3.20, 95% CI 0.33 to 30.94, 1 study, 25 women, low-quality evidence), hirsutism (OR 2.31, 95% CI 0.22 to 23.89, 1 study, 25 women, low-quality evidence).There appeared to be little or no difference in improvement of androgenic symptoms when LOD was compared to transvaginal ultrasound-guided LOD, with respect to hirsutism (OR 1.09, 95% CI 0.30 to 3.91, 1 study, 39 women, low-quality evidence) or acne (OR 0.84, 95% CI 0.20 to 3.50, 1 study, 31 women, low-quality evidence). HarmsLOD was associated with fewer gastrointestinal side effects than metformin plus clomiphene (OR 0.05, 95% CI 0.01 to 0.36, 2 studies, 332 women, I = 0%, moderate-quality evidence). One study suggested little or no difference in rates of ovarian hyperstimulation syndrome between LOD and gonadotrophins (OR 0.08, 95% CI 0.00 to 1.61, 1 study, 33 women, low-quality evidence).There were fewer adhesions with transvaginal hydrolaparoscopy compared to LOD (OR 0.10, 95% CI 0.05 to 0.18, 1 study, 246 women, moderate-quality evidence). There appeared to be little or no difference in adhesions when variable energy LOD was compared with standard LOD (OR 0.96, 95% CI 0.32 to 2.88, 1 study, 64 women, low-quality evidence). Another study (44 women) reported that none of the women who returned for surgery following either traditional or unilateral LOD were found to have adhesions.
AUTHORS' CONCLUSIONS
There was no clear evidence that LOD improves menstrual regularity or the androgenic symptoms of PCOS, compared to most of the medical treatments used in the included studies. LOD was associated with fewer gastrointestinal side effects compared to metformin and clomiphene.There was also no clear evidence of different effectiveness between types of LOD, except that LOD with four to five punctures per ovary may be more effective than two or fewer punctures. There was little evidence comparing LOD with different types of surgery, although one study concluded that transvaginal hydrolaparoscopy had a lower risk of adhesions than LOD.There was evidence from one small study of benefit from LOD compared to gonadotrophins for menstrual regulation. However, gonadotrophins are seldom used for this indication.
Topics: Acne Vulgaris; Clomiphene; Female; Gonadotropins; Hirsutism; Humans; Laparoscopy; Letrozole; Menstruation Disturbances; Metformin; Nitriles; Ovary; Polycystic Ovary Syndrome; Punctures; Randomized Controlled Trials as Topic; Triazoles
PubMed: 29125183
DOI: 10.1002/14651858.CD009526.pub2 -
Ultrasound in Obstetrics & Gynecology :... Jan 2018To compare the impact of clomiphene citrate (CC) vs other drug regimens on mid-cycle endometrial thickness (EMT), ovulation, pregnancy and live birth rates in women with... (Comparative Study)
Comparative Study Meta-Analysis Review
OBJECTIVES
To compare the impact of clomiphene citrate (CC) vs other drug regimens on mid-cycle endometrial thickness (EMT), ovulation, pregnancy and live birth rates in women with World Health Organization (WHO) group II ovulatory disorders.
METHODS
We searched MEDLINE, EMBASE, Scopus, Web of Science, The Cochrane Central Register of Clinical Trials (CENTRAL) and the non-MEDLINE subset of PubMed from inception to December 2016 and cross-checked references of relevant articles. We included only randomized controlled trials (RCTs) comparing CC used alone vs other drug regimens for ovulation induction in women with WHO group II anovulation. Outcomes were mid-cycle EMT, ovulation, pregnancy and live birth rates. We pooled weighted mean differences (WMD) with 95% confidence intervals (CI) for continuous variables (EMT) and risk ratios (RR) with 95% CI for binary variables (ovulation, pregnancy and live birth rates).
RESULTS
We retrieved 1718 articles of which 33 RCTs (4349 women, 7210 ovulation induction cycles) were included. In 15 RCTs that compared CC with letrozole, EMT was lower in the CC group (1957 women, 3892 cycles; WMD, -1.39; 95% CI, -2.27 to -0.51; I = 100%), ovulation rates after CC and letrozole were comparable (1710 women, 3217 cycles; RR, 0.97; 95% CI, 0.90-1.04; I = 47%), while CC led to a lower pregnancy rate (1957 women, 3892 cycles; RR, 0.78; 95% CI, 0.63-0.95; I = 43%) and a lower live birth rate (RR, 0.70; 95% CI, 0.49-0.98; I = 35%). In two RCTs that compared CC with CC plus metformin, EMT, ovulation and pregnancy rates were comparable (101 women, 140 cycles; WMD, -0.23; 95% CI, -0.92 to 0.45; I = 78%; RR, 0.84; 95% CI, 0.67-1.06; I = 0%; and RR, 0.79; 95% CI, 0.33-1.87; I = 0%). In three studies that compared CC with CC plus N-acetyl cysteine (NAC), EMT was lower in the CC group (340 women, 300 cycles; WMD, -1.51; 95% CI, -1.98 to -1.04; I = 45%). In two studies that compared CC with CC + nitric oxide (NO) donor, EMT was lower in the CC group (120 women, 304 cycles; WMD, -1.75; 95% CI, -2.08 to -1.41; I = 0%). Compared with CC plus NO donor or NAC, CC showed statistically significant lower ovulation and pregnancy rates. Compared with tamoxifen in three studies, CC showed a tendency towards lower EMT (571 women, 844 cycles; WMD, -1.34; 95% CI, -2.70 to 0.01; I = 96%) with comparable ovulation and pregnancy rates.
CONCLUSIONS
In women with WHO group II ovulatory disorders, ovulation induction with CC might result in lower EMT than other ovulation induction regimens. Whether the lower EMT caused the lower pregnancy and live birth rates remains to be elucidated. Letrozole seems to be beneficial for these women. However, our findings should be interpreted with caution as the quality of evidence was very low. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.
Topics: Anovulation; Birth Rate; Clomiphene; Endometrium; Estrogen Antagonists; Female; Fertility Agents, Female; Humans; Infant, Newborn; Live Birth; Ovulation Induction; Pregnancy; Pregnancy Outcome; Pregnancy Rate; Randomized Controlled Trials as Topic; Tamoxifen
PubMed: 29055102
DOI: 10.1002/uog.18933 -
Reproductive Biology and Endocrinology... Feb 2017Polycystic ovary syndrome (PCOS) is a common endocrine disorder, affecting 9-18% of women in reproductive age that causes hyperandrogenism and infertility due to... (Review)
Review
Polycystic ovary syndrome (PCOS) is a common endocrine disorder, affecting 9-18% of women in reproductive age that causes hyperandrogenism and infertility due to dysfunctional follicular maturation and anovulation. The etiology of PCOS is still poorly known, and information from experimental animal models may help improve current understanding of the mechanisms of PCOS initiation and development. Therefore, we conducted a systematic review of currently available methods for simulation of PCOS in experimental models, focusing on two main endocrine traits: ovarian morphology changes and circulating levels of sex hormones and gonadotropins.We searched the MEDLINE database for articles in English or Spanish published until October 2016. Of 933 studies identified, 39 were included in the systematic review. One study compared interventions with androgens versus estrogens, 18 used androgen-induced stimulation, 9 used estrogens or drugs with estrogen action, including endocrine disruptors, to induce PCOS-like models, and 12 used miscellaneous interventions. Broad differences were found among the studies concerning hormonal interventions, animal species, and developmental stage at the time of the experiments, and most models resulted in ovarian morphology changes, mainly increases in the number of cystic and antral follicles and decreases in the corpus luteum. Hyperandrogenism was produced by using androgens and other drugs as the stimulatory agent. However, studies using drugs with estrogenic effect did not observe changes in circulating androgens.In conclusion, medium- or long-term testosterone administration in the pre- and postnatal periods performed best for induction of a PCOS-like phenotype, in rhesus macaque and rat models respectively. In rats, postnatal exposure to androgens results in reprogramming of the hypothalamic-pituitary-ovarian-axis. Thus, comparisons between different intervention models may be useful to define the timing of reproductive PCOS phenotypes in experimental animal models.
Topics: Animals; Disease Models, Animal; Female; Gonadal Steroid Hormones; Gonadotropins; Humans; Hyperandrogenism; MEDLINE; Ovary; Polycystic Ovary Syndrome
PubMed: 28183310
DOI: 10.1186/s12958-017-0231-z -
BMJ (Clinical Research Ed.) Jan 2017To compare the effectiveness of alternative first line treatment options for women with WHO group II anovulation wishing to conceive. (Review)
Review
OBJECTIVE
To compare the effectiveness of alternative first line treatment options for women with WHO group II anovulation wishing to conceive.
DESIGN
Systematic review and network meta-analysis.
DATA SOURCES
Cochrane Central Register of Controlled Trials, Medline, and Embase, up to 11 April 2016.
STUDY SELECTION
Randomised controlled trials comparing eight ovulation induction treatments in women with WHO group II anovulation: clomiphene, letrozole, metformin, clomiphene and metformin combined, tamoxifen, gonadotropins, laparoscopic ovarian drilling, and placebo or no treatment. Study quality was measured on the basis of the methodology and categories described in the Cochrane Collaboration Handbook. Pregnancy, defined preferably as clinical pregnancy, was the primary outcome; live birth, ovulation, miscarriage, and multiple pregnancy were secondary outcomes.
RESULTS
Of 2631 titles and abstracts initially identified, 54 trials reporting on 7173 women were included. All pharmacological treatments were superior to placebo or no intervention in terms of pregnancy and ovulation. Compared with clomiphene alone, both letrozole and the combination of clomiphene and metformin showed higher pregnancy rates (odds ratio 1.69, 95% confidence interval 1.33 to 2.14; 1.71, 1.28 to 2.27; respectively). Letrozole led to higher live birth rates when compared with clomiphene alone (1.67, 1.11 to 2.49). Metformin led to lower multiple pregnancy rates compared with clomiphene alone (0.22, 0.05 to 0.93).
CONCLUSIONS
In women with WHO group II anovulation, letrozole and the combination of clomiphene and metformin are superior to clomiphene alone in terms of pregnancy. Compared with clomiphene alone, letrozole is the only treatment showing a significantly higher rate of live birth.
SYSTEMATIC REVIEW REGISTRATION
PROSPERO CRD42015027579.
READERS' NOTE
This is the second version of this paper. The original version was corrected following the retraction of two studies and removal of another which were ineligible (references 40, 41, and 75 of the original paper). These studies are not shown in this version. A tracked changes version of the original version is attached as a supplementary file to the correction notice, which explains the issue further.
Topics: Anovulation; Clomiphene; Drug Therapy, Combination; Female; Humans; Infertility, Female; Letrozole; Metformin; Network Meta-Analysis; Nitriles; Ovulation Induction; Pregnancy; Pregnancy Rate; Treatment Outcome; Triazoles
PubMed: 28143834
DOI: 10.1136/bmj.j138 -
The Cochrane Database of Systematic... Jan 2017Clomiphene citrate (CC) is generally considered first-line treatment in women with anovulation due to polycystic ovary syndrome (PCOS). Ovulation induction with... (Meta-Analysis)
Meta-Analysis Review
Metformin during ovulation induction with gonadotrophins followed by timed intercourse or intrauterine insemination for subfertility associated with polycystic ovary syndrome.
BACKGROUND
Clomiphene citrate (CC) is generally considered first-line treatment in women with anovulation due to polycystic ovary syndrome (PCOS). Ovulation induction with follicle-stimulating hormone (FSH; gonadotrophins) is second-line treatment for women who do not ovulate or conceive while taking CC. Metformin may increase the effectiveness of ovulation induction with gonadotrophins and may promote safety by preventing multiple pregnancy.
OBJECTIVES
To determine the effectiveness and safety of metformin co-treatment during ovulation induction with gonadotrophins with respect to rates of live birth and multiple pregnancy in women with PCOS.
SEARCH METHODS
We searched the Cochrane Gynaecology and Fertility (CGF) Group specialised register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, PsycINFO and the Cumulative Index to Nursing and Allied Health Literature (CINAH) on 8 June 2016, and the reference lists of included and other relevant studies. We searched ongoing trials registries in the World Health Organization (WHO) portal and on clinicaltrials.gov on 4 September 2016.
SELECTION CRITERIA
We included randomised controlled trials (RCTs) reporting data on comparison of clinical outcomes in women with PCOS undergoing ovulation induction with gonadotrophins plus metformin versus gonadotrophins alone or gonadotrophins plus placebo.
DATA COLLECTION AND ANALYSIS
We used standard methodological procedures recommended by Cochrane. Primary review outcomes were live birth rate and multiple pregnancy rate. Secondary outcomes were ovulation rate, clinical pregnancy rate, ovarian hyperstimulation syndrome (OHSS) rate, miscarriage rate, cycle cancellation rate and adverse effects.
MAIN RESULTS
We included five RCTs (with 264 women) comparing gonadotrophins plus metformin versus gonadotrophins. The gonadotrophin used was recombinant FSH in four studies and highly purified FSH in one study. Evidence was of low quality: The main limitations were serious risk of bias due to poor reporting of study methods and blinding of participants and outcome assessors. Live birth Metformin plus FSH was associated with a higher cumulative live birth rate when compared with FSH (odds ratio (OR) 2.31, 95% confidence interval (CI) 1.23 to 4.34; two RCTs, n = 180; I = 0%; low-quality evidence). This suggests that if the chance of live birth after FSH is assumed to be 27%, then the chance after addition of metformin would be between 32% and 60%. Other pregnancy outcomes Metformin use was associated with a higher ongoing pregnancy rate (OR 2.46, 95% CI 1.36 to 4.46; four RCTs, n = 232; I = 0%; low-quality evidence) and a higher clinical pregnancy rate (OR 2.51, 95% CI 1.46 to 4.31; five RCTs, n = 264; I = 0%; low-quality evidence). Multiple pregnancy Results showed no evidence of a difference in multiple pregnancy rates between metformin plus FSH and FSH (OR 0.55, 95% CI 0.15 to 1.95; four RCTs, n = 232; I = 0%; low-quality evidence) and no evidence of a difference in rates of miscarriage or OHSS. Other adverse effects Evidence was inadequate as the result of limited available data on adverse events after metformin compared with after no metformin (OR 1.78, 95% CI 0.39 to 8.09; two RCTs, n = 91; I = 0%; very low-quality evidence).
AUTHORS' CONCLUSIONS
Preliminary evidence suggests that metformin may increase the live birth rate among women undergoing ovulation induction with gonadotrophins. At this moment, evidence is insufficient to show an effect of metformin on multiple pregnancy rates and adverse events. Additional trials are necessary before we can provide further conclusions that may affect clinical practice.
Topics: Coitus; Combined Modality Therapy; Drug Therapy, Combination; Female; Fertility Agents, Female; Fertilization in Vitro; Follicle Stimulating Hormone; Gonadotropins; Humans; Infertility, Female; Live Birth; Metformin; Ovulation Induction; Polycystic Ovary Syndrome; Pregnancy; Pregnancy Outcome; Pregnancy Rate; Pregnancy, Multiple; Randomized Controlled Trials as Topic
PubMed: 28118681
DOI: 10.1002/14651858.CD009090.pub2 -
The Cochrane Database of Systematic... Dec 2016Subfertility due to anovulation is a common problem in women. First-line oral treatment is with antioestrogens such as clomiphene citrate, but resistance may be apparent... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Subfertility due to anovulation is a common problem in women. First-line oral treatment is with antioestrogens such as clomiphene citrate, but resistance may be apparent with clomiphene. Alternative and adjunctive treatments have been used including tamoxifen, dexamethasone, and bromocriptine. The effectiveness of these is to be determined.
OBJECTIVES
To determine the relative effectiveness of antioestrogen agents including clomiphene alone or in combination with other medical therapies in women with subfertility associated with anovulation, possibly caused by polycystic ovarian syndrome.
SEARCH METHODS
We conducted a search of the Cochrane Gynaecology and Fertility Group Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, PsycINFO, and CINAHL (all from inception to August 2016) to identify relevant randomised controlled trials (RCTs). We searched the United Kingdom National Institute for Clinical Excellence (NICE) guidelines and the references of relevant reviews and RCTs. We also searched the clinical trial registries for ongoing trials (inception until August 2016).
SELECTION CRITERIA
We considered RCTs comparing oral antioestrogen agents for ovulation induction (alone or in conjunction with medical therapies) in anovulatory subfertility. We excluded insulin-sensitising agents, aromatase inhibitors, and hyperprolactinaemic infertility.
DATA COLLECTION AND ANALYSIS
Two review authors independently performed data extraction and quality assessment. The primary outcome was live birth; secondary outcomes were pregnancy, ovulation, miscarriage, multiple pregnancy, ovarian hyperstimulation syndrome, and adverse effects.
MAIN RESULTS
This is a substantive update of a previous review. We identified an additional 13 studies in the 2016 update. The review now includes 28 RCTs (3377 women) and five RCTs awaiting classification. Five of the 28 included trials reported live birth/ongoing pregnancy. Secondary outcomes were poorly reported.The quality of the evidence ranged from low to very low. The primary reasons for downgrading the evidence were imprecision and risk of bias associated with poor reporting. Antioestrogen versus placebo Live birth rate, miscarriage rate, multiple pregnancy rate, and ovarian hyperstimulation syndrome (OHSS)No data were reported for these outcomes. Clinical pregnancy rateClomiphene citrate was associated with an increased chance of a clinical pregnancy compared with placebo, though the size of the benefit was very uncertain (odds ratio (OR) 5.91, 95% confidence interval (CI) 1.77 to 19.68; 3 studies; 133 women; low-quality evidence). If the chance of a clinical pregnancy was 5% in the placebo group, then between 8% and 50% of women would have a clinical pregnancy in the clomiphene group. Clomiphene citrate versus tamoxifen Live birth rateThere was no clear evidence of a difference in the chance of a live birth between the clomiphene citrate and tamoxifen groups (OR 1.24, 95% CI 0.59 to 2.62; 2 studies; 195 women; low-quality evidence). If 20% of women in the tamoxifen group had a live birth, then between 13% and 40% of women in the clomiphene citrate group would have a live birth. Miscarriage rateThere was no clear evidence of a difference in the chance of a miscarriage between the clomiphene citrate and tamoxifen groups (OR 1.81, 95% CI 0.80 to 4.12; 4 studies; 653 women; low-quality evidence). If 3% of women in the tamoxifen group had a miscarriage, then between 2% and 10% in the clomiphene citrate group would have a miscarriage. Clinical pregnancy rateThere was no clear evidence of a difference in the chance of a clinical pregnancy between the clomiphene citrate and tamoxifen groups (OR 1.30, 95% CI 0.92 to 1.85; 5 studies; 757 women; I = 69%; low-quality evidence). If 22% of women in the tamoxifen group had a clinical pregnancy, then between 21% and 35% in the clomiphene citrate group would have a clinical pregnancy. Multiple pregnancy rate There was insufficient evidence of a difference in the chance of a multiple pregnancy between the clomiphene citrate group (OR 2.34, 95% CI 0.34 to 16.04; 3 studies; 567 women; very low-quality evidence). If 0% of women in the tamoxifen group had a multiple pregnancy, then between 0% and 0.5% of women in the clomiphene group would have a multiple pregnancy. OHSSThere were no instances of OHSS in either the clomiphene citrate or the tamoxifen group reported from three studies. Clomiphene citrate with tamoxifen versus tamoxifen alone Clinical pregnancy rateThere was insufficient evidence to determine whether there was a difference between groups (OR 3.32, 95% CI 0.12 to 91.60; 1 study; 20 women; very low-quality evidence). No data were reported for the other outcomes. Other comparisons of interestLimited evidence suggested that compared with a gonadotropin, clomiphene citrate was associated with a reduced chance of a pregnancy, ongoing pregnancy, or live birth, with no clear evidence of a difference in multiple pregnancy rates.The comparison of clomiphene citrate plus medical adjunct versus clomiphene alone was limited by the number of trials reporting the comparison and poor reporting of clinical outcomes relevant to this systematic review and by the number of adjuncts reported (ketoconazole, bromocriptine, dexamethasone, combined oral contraceptive, human chorionic gonadotropin, hormone supplementation). The addition of dexamethasone or combined oral contraceptive suggested a possible benefit in pregnancy outcomes, but findings were very uncertain and further research is required to confirm this.There was limited evidence suggesting that a 10-day regimen of clomiphene citrate improves pregnancy outcomes compared with a 5-day regimen. Data for early versus late regimens of clomiphene citrate were insufficient to be able to make a judgement on differences for pregnancy outcomes.
AUTHORS' CONCLUSIONS
We found evidence suggesting that clomiphene citrate improves the chance of a clinical pregnancy compared with placebo, but may reduce the chance of live birth or ongoing pregnancy when compared with a gonadotropin. Due to low event rates, we advise caution interpreting these data.The comparison of clomiphene citrate plus medical adjunctive versus clomiphene alone was limited by the number of trials reporting the comparison. The evidence was very low quality and no firm conclusions could be drawn, but very limited evidence suggested a benefit from adjunctive dexamethasone or combined oral contraceptives. Low-quality evidence suggested that a 10-day regimen of clomiphene citrate improves pregnancy rates compared with a 5-day regimen, but further research is required.
Topics: Anovulation; Clomiphene; Contraceptives, Oral, Combined; Dexamethasone; Drug Therapy, Combination; Estrogen Antagonists; Female; Gonadotropins; Humans; Infertility, Female; Live Birth; Polycystic Ovary Syndrome; Randomized Controlled Trials as Topic; Tamoxifen
PubMed: 27976369
DOI: 10.1002/14651858.CD002249.pub5