Obel 1993.

Methods	Randomisation: method and concealment of allocation not reported Single‐centre, parallel group and placebo‐controlled design with double blinding Number of women randomised: 151 Number of withdrawals: 22 (group 1: 5 because of AEs, 1 because of breast cancer, 5 for reasons unrelated to treatment, total 11; group 2: 3 because of AEs, 2 because of carcinoma, total 5; group 3: 1 because of AEs, 1 because of anxiety, 1 for reasons unrelated to treatment, total 3) Source of funding: not reported
Participants	Country: Denmark Volunteers with early menopause (last spontaneous vaginal bleeding > 6 and < 24 months earlier) and with no use of HT during preceding 24 months recruited from Frederiksborg County Exclusion criteria: previous or current estrogen‐dependent neoplasia; thromboembolic disease, liver or pancreatic disease, diabetes mellitus, severe obesity, diseases with high or low bone turnover and medication known to influence bone metabolism or provoke induction of liver enzymes
Interventions	Continuous vs sequential vs placebo (1) Continuous: 2 mg E2 + 1 mg NETA (Kliogest) daily (2) Sequential: 2 mg E2 days 1 to 12, E2 2 mg + 1 mg NETA days 13 to 22, 1 mg E2 days 23 to 28 (3) Control: placebo Duration: 2 years
Outcomes	Frequency of endometrial hyperplasia, carcinoma, or both, at 2 years Frequency of irregular bleeding Non‐adherence to therapy
Power calculation described	No
Analysis by Intention to Treat	No
Notes	Some of the data was read off the graphs
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Method of sequence generation not described
Allocation concealment (selection bias)	Unclear risk	Not described
Blinding (performance bias and detection bias) All outcomes	Low risk	Blinding
Incomplete outcome data (attrition bias) All outcomes	Low risk	Endometrial biopsies on 96 of the 151 women randomised (64%) after 2 years
Other bias	Low risk	3 parallel groups described as having 'no inter‐group differences'