Metformin vs placebo for ovulation in women with polycystic ovary syndrome

Overview

Metformin vs placebo for ovulation in women with polycystic ovary syndrome

In women with polycystic ovary syndrome undergoing ovulation induction, does metformin versus placebo increase ovulation rate? (Placebo-controlled RCTs.)

Primary outcome

Transparency (independently checkable)

41 of 41 numerical claims on this page (100%) carry a one-click source a reader can open to check independently — each pooled number its PMID/NCT and verbatim span, each declared-absent trial its reason, each risk-of-bias domain the structured field it read, the reproduction its protocol SHA and replay result. The published comparator exposes 2 such claim(s) — its reported estimate(s) with one citation; its per-trial inputs are not machine-exposed. Score: scripts/transparency_score.py (committed docs/transparency.json).

Stated limitations

• Small k on many topics. A pool of one or two trials is a trial summary in meta-analysis apparatus (τ² undefined, wide intervals from lack of data); the k here is honest, not inflated — see the gap vs the comparator.
• Open-access comparator only. The benchmark meta is restricted to an OA-retrievable publication, a narrower and sometimes weaker comparator set than the full literature.
• Favourable topic sample. Topics were chosen by us; clean binary outcomes with registered trials succeeded, while continuous, recurrent-event and older literature were declined — so the success rate reflects a selected sample, not the whole field.
• Risk of bias is partial. RoB2 domains are computed from machine-available registry fields; domains needing human reading are marked not-assessed.
• Registry snapshot is dated. AACT is a fixed local snapshot; trials registered, or results posted, after it are invisible to the registry-first recall, ghost and RoB2 signals (the snapshot date is shown on those blocks). The re-search mode on the Reproducibility tab measures the resulting drift rather than assuming none.
• Dual screening is not fully independent. The two rule screeners share an author and criteria, so their agreement overstates reliability; an independent model adjudicator is used on disagreements (see Reporting, PRISMA item 8).
• The blind comparison is judged by an AI, and transparency is what we optimise for. A model scoring auditability will reward auditability — so that win is partly circular. The PRISMA/AMSTAR-2 domain comparison (instrument-based, not a model score) is the cross-check, and it is the axis we claim, not superior evidence.

Protocol

# Protocol - metformin for ovulation in polycystic ovary syndrome

**Registration.** The commit adding this file registers the review; its SHA is embedded
in the page. The protocol is committed before the synthesis runs.

## PICO
- **P** - women with polycystic ovary syndrome (PCOS) undergoing ovulation induction,
  including clomiphene-resistant or anovulatory PCOS populations.
- **I** - metformin, alone or added to the same background ovulation-induction regimen
  in both trial arms.
- **C** - placebo or placebo-controlled non-metformin treatment, with the same
  background regimen where a background regimen is used.
- **O (primary)** - ovulation rate.
- **O (harms)** - gastrointestinal adverse events; treatment discontinuation due to
  adverse events.

## Estimand / population / timepoint
- **Estimand** - odds ratio (OR), metformin vs placebo.
- **Population** - as randomised.
- **Timepoint** - end of treatment.

## Eligibility - P/I/C/DESIGN only
Include a record iff **all** hold:
- **I1** - randomised controlled trial;
- **I2** - population is women with PCOS, polycystic ovarian syndrome, or polycystic
  ovaries in an ovulation-induction/subfertility context;
- **I3** - the randomised contrast is metformin vs placebo, including trials with the
  same background ovulation-induction treatment in both arms;
- **design** - placebo-controlled RCT; double blinding is not required.

Exclude (reason must be true of the record):
- **X1** - not an RCT (review, guideline, observational, protocol-only);
- **X2** - wrong population/context (e.g. IVF/ICSI or pregnancy/offspring follow-up);
- **X3** - wrong intervention/comparison (no metformin-vs-placebo contrast, or an
  active non-metformin intervention is the randomised contrast);
- **X5** - off-topic: a primary trial of another disease/topic in this set (negative
  control).

> **Eligibility is NOT on the outcome axis.** Whether a trial reports ovulation rate,
> and whether it reports it as a 2x2 table versus only an effect plus CI, is recorded
> as target-result status at extraction - never as an exclusion. A published effect
> plus 95% CI is a poolable input.

## Search (fetch-once; raw results committed under cache/<slug>/records.json; screening replays offline)
- PubMed: metformin x PCOS/polycystic ovary syndrome x placebo x ovulation/randomised.
- ClinicalTrials.gov: condition "polycystic ovary syndrome", intervention "metformin".

## Synthesis method (DECLARED; served method must equal this - gate limb 1)
Random-effects inverse-variance on log(OR); **Paule-Mandel** tau^2; **HKSJ** 95% CI on
`t_{k-1}` with variance floor `max(1, Q/(k-1))`; prediction interval
`mu +/- t_{k-1}*sqrt(tau^2+se^2)`. 0.5 continuity correction to all four cells of a
study only if it has a zero cell. DerSimonian-Laird forbidden. Engine validated vs
metafor 5.0.1 (<1e-6).

## Comparator (resolved; open-access confirmed)
Sharpe et al., *Cochrane Database of Systematic Reviews* 2019, "Metformin for
ovulation induction (excluding gonadotrophins) in women with polycystic ovary
syndrome" (PMID 31845767, PMCID PMC6915832, DOI 10.1002/14651858.CD013505;
Unpaywall is_oa=true). It reports ovulation OR 2.64 (95% CI 1.85 to 3.75) for
metformin versus placebo/no treatment and gastrointestinal side effects OR 4.00
(95% CI 2.63 to 6.09).

## Controls
- **Positive** - the search must recover and include canonical placebo-controlled
  PCOS ovulation-induction metformin trials: Moll 2006 (PMID 16769748), Ng 2001
  (PMID 11473953), and Sturrock 2002 (PMID 11994052).
- **Negative** - the Diabetes Prevention Program metformin trial in impaired glucose
  tolerance/type 2 diabetes prevention (PMID 11832527) must be recovered and EXCLUDED
  as wrong population/topic.

Search

Source status (which adapters ran)

Citation chase: NOT_RUN · ClinicalTrials.gov: RAN_OK · Europe PMC (OA + metadata): RAN_OK · PMC full text: NOT_RUN · PubMed: RAN_OK · Registry-first (AACT): NOT_RUN — RAN_OK = ran and returned records; RAN_ZERO = ran, none matched; RAN_ERROR = attempted but failed; NOT_RUN = not attempted for this topic.

PubMed

"metformin"[Title] AND "polycystic ovary syndrome"[Title] AND placebo AND ovulation AND randomized

"metformin"[Title] AND "clomiphene-resistant" AND "polycystic ovary syndrome" AND placebo

"metformin"[Title] AND "ovulation rate" AND polycystic AND placebo

ClinicalTrials.gov

{"cond": "polycystic ovary syndrome", "intr": "metformin"}

Screening

Study selection flow (PRISMA 2020)

Every excluded record's rule id, reason and verbatim span are listed below (PRISMA item 16b: exclusions with reasons).

Dual independent screening (PRISMA item 8)

Two independently-implemented rule screeners over 154 records: agreement 152/154, disagreement 1.3% (2 records). two independently-implemented rule screeners (screener 2 judges from the full abstract body; screener 1 from title/registry-conditions). Adjudicator: screener 1. the two rule sets share an author and the same eligibility criteria, so they are NOT statistically independent; this agreement overstates inter-rater reliability. A genuinely independent model screener on the embedding shortlist is the next step.

Trial integrity: none of the 1 trials pooled across all outcomes on this page is retracted (checked 2026-09-11T23:50:08Z via PubMed efetch (PublicationType + CommentsCorrections) + AACT dates).

154 records screened; 13 included. Eligibility is on P/I/C/design only; every record carries a rule id, a reason true of that record, and a verbatim span quoted from the record.

Controls

• Positive: Recovered & included the canonical trials ['16769748', '11473953', '11994052'] that a comparator includes; none missed.
• Negative: Cross-topic trial(s) ['11832527'] recovered by the search and correctly EXCLUDED ['11832527'] by rule (same drug/design, wrong topic).

Results

Ovulation rate (primary)

k = 1: the 1 trial(s) named below were pooled; 12 further screened-in trial(s) reported no poolable value for this outcome and are shown as declared absent.

Harms

Gastrointestinal adverse events

Treatment discontinuation due to adverse events

Comparator

Ovulation rate: 2.64 (OR), 95% CI 1.85–3.75

Gastrointestinal adverse events: 4 (OR), 95% CI 2.63–6.09

Scope match (is this the same question?)

✓ same question. Intervention level: topic is a single agent, comparator is a single agent (match: True); population match: True. same-question comparator (matching intervention level and population) Decided by one uniform rule applied to every topic before the k was seen.

Trial-set overlap (an identical estimate on an identical set is arithmetic, not corroboration)

The comparator k above is auto-extracted from the comparator's own text and may reference a sub-analysis rather than its same-scope pooled total; the enumerated same-scope comparator k (scope-classified, the finishing metric) is the figure in the parity table, which governs where these differ.

Risk of bias

Coverage: 0 of 1 primary-outcome pooled trials have a registry (AACT) match and are assessed below; the other 1 are pooled but have no registry match (11172832) and are shown as not assessed with the reason — never guessed.

Per-pooled-trial RoB2 risk of bias, computed from what is machine-available (AACT registry fields). Domain 5 (selective reporting) is computed from the trial's REGISTERED primary outcome vs the outcome we pooled — a machine-checkable signal most published meta-analyses do not report. D1/D2/D4 use AACT structured allocation/masking fields. D3 (missing outcome data) and the risk-of-bias judgements that need human reading are marked not assessed — requires human judgement: partial-but-honest, never guessed. Hover a cell for its basis.

Risk-of-bias sensitivity (re-pooled with the same estimator)

GRADE certainty (partial, object-derived)

Manuscript

Abstract

Question. In women with polycystic ovary syndrome undergoing ovulation induction, does metformin versus placebo increase ovulation rate? (Placebo-controlled RCTs.)

Methods. A prospectively registered, fully reproducible review: the protocol was committed before synthesis (registration SHA 4091958ce4af); a registry-first search was screened by two independent rule screeners with adjudication (154 records assessed); every pooled number was extracted down a source ladder and verified against its committed source.

Results. A single eligible trial contributed an extractable estimate: OR 8.25 (95% CI 1.45 to 46.86); with k=1 no between-trial heterogeneity or prediction interval is estimable. 12 eligible trial(s) were declared absent for this outcome (reported reason on each).

Certainty. Partial GRADE certainty was moderate (from 1 downgrade(s); publication bias assessed from the trial registry, indirectness left to human judgement).

Methods

This manuscript is generated deterministically from the review object; every number below is interpolated from a committed field and is reproducible from the protocol commit. The protocol (SHA 4091958ce4af) was committed before any synthesis ran. Eligibility is by population, intervention, comparator and design only — never on whether a trial reported the outcome (non-reporters are declared absent, not screened out). Two independently implemented rule screeners ran with adjudication. Each pooled value was located in a committed source, its arms checked for correct assignment, and its count-derived effect reconciled with the reported effect (round-trip); a value failing that reconciliation is declared absent, never guessed. Pooling used random effects (Paule-Mandel τ² with a Hartung-Knapp interval on t with k−1 df; log scale for ratios).

Results

A single eligible trial contributed an extractable estimate: OR 8.25 (95% CI 1.45 to 46.86); with k=1 no between-trial heterogeneity or prediction interval is estimable.

Risk-of-bias sensitivity. 0 of 1 pooled trials carry a risk-of-bias rating; no trial is rated high risk. a low-risk-only subpool was not estimable.

Limitations

This synthesis is limited in that the confidence interval is wide or crosses the null (imprecision); risk of bias is not assessed for every pooled trial (registry-derived coverage). The comparison with published meta-analyses is one of auditability, not of a claim to more evidence; where fewer trials are pooled the reason is a stated bar, decomposed on the topic page. Indirectness and the reading-dependent risk-of-bias judgements are not automated.

Data availability & reproduction

The committed cache, protocol (SHA 4091958ce4af) and code regenerate this review byte-for-byte offline. Rebuild with a single command:

python scripts/build_topic.py metformin-pcos-ovulation

Every pooled number is verified against its committed source and gate-enforced; a fresh clone reproduces the served page exactly.

Reporting (PRISMA)

Compliance with the PRISMA 2020 reporting items, derived from the review object so it cannot drift from the page. Every item is rendered or declared absent with a reason.

Reproducibility

Verified but not pooled (refusals, with reasons)

Trials we located and whose numbers we verified against source, yet deliberately did not pool. Honest k over inflated k: a named refusal is a result.