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Table 1 Characteristics of included studies

From: Metformin and gonadotropins for ovulation induction in patients with polycystic ovary syndrome: a systematic review with meta-analysis of randomized controlled trials

  Participants Outcomes Notes
De Leo et al[18] Sample size: - N. of ampoules of huFSH. Crossover study.
20 subjects - Serum E2 levels. No data on live-births.
Exclusion: - Days of treatment. No blind design.
- Abnormal FSH and/or prolactin levels. - Cancelled cycles. No criteria for defining OHSS.
- Abnormal thyroid function. - Incidence of OHSS. No criteria for cycle cancellation.
- Congenital adrenal hyperplasia. - Pregnancy rate.
- Abnormal partner’s seminal parameters. - Side effects.
- Drug assumption 2 mths prior to the study.
Yarali et al[19] Sample size: - N. of ampoules of rFSH. Data of spontaneous ovulation during the pre-treatment phase were excluded.
32 subjects - Serum E2 levels.  
Exclusion: - Days of treatment. No criteria for defining OHSS.
- Any infertility factor other than PCOS (by semen analysis, hysterosalpingography, and/or laparoscopy). - Cancelled cycles. No data on OHSS.
- Endocrinopathies. - Pregnancy rate. No data on live-births.
- Abnormal glucose tolerance, IGT or type-2 DM. - Endometrial thickness. Cycle was cancelled in presence of more than 3 follicles ≥15 mm, or in absence of ovarian response after 35 days of treatment.
- Use of medications known to alter insulin secretion or action. - Side effects.
Tasdemir et al[20] Sample size: - rFSH IU. No blind design.
32 subjects - serum E2 levels. No criteria for cycle cancellation.
Exclusion: - N. dominant follicles. No criteria for defining OHSS.
- Age <20 > 34. - Days of treatment. No data on live-births.
- Congenital adrenal hyperplasia. - Endometrial thickness. Not specified n. of side effects.
- Hyperprolactinemia. - Cancelled cycles.  
- Hypothyroidism. - Incidence of OHSS.  
- Abnormal renal and liver tests. - Pregnancy rate.
- Use of drugs with possible effect on endogenous sex hormones. - Multiple pregnancies.
- Type 1-2 DM. - Side effects.
- Hypophysal insufficiency.  
- Any infertility factor other than PCOS (by semen analysis, hysterosalpingography, and/or laparoscopy).  
Palomba et al[21] Sample size: - N. of ampoules of hpFSH. Only insulin-resistant women were included.
70 subjects - Serum E2 levels. IUI was performed in ovulating women who failed to conceive.
Exclusion: - N. dominant follicles. TI was performed in non-ovulating women.
- Age <20 or >34 years. - Days of treatment. Cycle was cancelled in presence of more than 3 follicles ≥14 mm, or in absence of ovarian response after 35 days of treatment.
- BMI >30 and <18 kg/m2. - Cancelled cycles.
- Neoplastic, metabolic (including glucose intolerance), hepatic, and cardiovascular disorder or other concurrent medical illness. - Incidence of OHSS.
- Hypothyroidism. - Ovulation rate.
- Hyperprolactinaemia. - Rate of mono-ovulatory cycles.
- Cushing’s syndrome; non-classical congenital adrenal - Pregnancy rate.
- hyperplasia. - Multiple pregnancy rate (primary end-point).
- Abuse of alcohol. - Abortion.
- Current or previous (within 6 mths) use of oral contraceptives, glucocorticoids, antiandrogens, antidiabetic, and anti-obesity and hormonal drugs. - Live-birth rate.
- Organic pelvic diseases. - Side effects.
- Previous pelvic surgery.
- Suspected peritoneal factor infertility.
- Tubal or male factor infertility (by hysterosalpingogram and semen analysis).
- Intention to start a diet or a specific program of physical activity.
van Santbrink et al[22] Sample size: - Units of rFSH (primary end-point). Only insulin-resistant women were included.
20 subjects - Serum E2 levels. No clear definition for CC-resistance and CC-failure.
Exclusion: - Days of treatment (primary end-point).
- Age ≤18 ≥ 37 yrs - Cancelled cycles. No specific definition for PCOS.
- Abnormal serum E2 and FSH levels. - Incidence of OHSS. No criteria for defining OHSS.
- Abnormal serum prolactin and thyroxine levels. - Ovulation rate. No specification of the time of metformin and placebo administration.
- DM. - Rate of mono-ovulatory cycles.
- Signs of liver or kidney insufficiency and heart or vascular disease. - Pregnancy rate. The study was divided into two phases. Only the 2nd phase was considered in the analysis.
- Multiple pregnancy rate.
- Abortion. No data on live-births.
- Serious side effects. Cycle was cancelled in presence of more than 3 follicles ≥15 mm, or in absence of ovarian response at the maximum dosage (225IU rFSH daily).
Cheng et al[23] Sample size: - N. of ampoules of HMG. No data on the days of treatment.
60 subjects - Serum E2 levels. No data of the multiple pregnancies.
Exclusion: - N. dominant follicles. No data on live-births.
- Age ≥ 40 yrs. - Cancelled cycles. No data on side effects.
- Endometrial pathology. - Incidence of OHSS. No criteria for defining OHSS.
- Abnormal glucose tolerance (75g OGTT). - Ovulation rate. Cycle was cancelled in presence of more than 4 dominant follicles.
- Any infertility factor other than PCOS. - Rate of mono-ovulatory cycles.
- Other common causes of hyperandrogenism. - Pregnancy rate (primary end-point).
- Prolactinoma.
- Congenital adrenal hyperplasia.
- Cushing syndrome.
- Virilizing ovarian or adrenal tumours.
- Hormonal drugs assumption 3 mths prior to the study.
Begum et al[24] Sample size: - Ovulation rate. No blind design.
110 subjects - Miscarriage. No criteria for defining OHSS.
Exclusion: - Perinatal outcome. No criteria for cycle cancellation due to hyper-response.
-DM. - Pregnancy rate (primary end-point).
- Altered glucose metabolism. - Live-birth rate (primary end-point). No clear strategy (TI or IUI).
- Hyperprolactinemia.
- Hypothyroidism.
- Endometriosis.
- Pelvic inflammatory disease.
- Tubal factor infertility.
- Partner abnormal semen parameters.
  1. BMI: body mass index; CC: clomiphene citrate; DM: diabetes mellitus; E2: estradiol; GIR: glucose to insulin ratio; HMG: human menopausal gonadotropins; hpFSH: human purified follicle-stimulating hormone; huFSH: human urinary FSH; IGT: impaired glucose tolerance; IUI: intrauterine insemination; LH: luteinizing hormone; OGTT: oral glucose tolerance test; OHSS: ovarian hyper-stimulation syndrome; PCOS: polycystic ovary syndrome; rFSH: recombinant FSH; SHBG: sex-hormone binding globulin; TI: timed intercourse.