Placebo116
CEE only45
CEE + MPA (cyclical)112
CEE + MPA (continuous)119
CEE + MP114
Total no. (%)506 (84.9)
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Therapy Areas
Utrogestan® 100mg (micronised progesterone)
efficacy
Empower her to own her menopause
Utrogestan® 100mg (micronised progesterone) efficacy
Utrogestan 100mg is indicated for adjunctive use with oestrogen in postmenopausal women with an intact uterus, as hormone replacement therapy (HRT).2
Utrogestan 100mg greatly reduces the oestrogen-induced risk of endometrial hyperplasia in non-hysterectomised women.2
Combining oestrogen with progesterone protects the endometrium from hyperplastic changes associated with oestrogen-only therapy.2
Utrogestan 100mg greatly reduces the oestrogen-induced risk of endometrial hyperplasia in non-hysterectomised women.2
Combining oestrogen with progesterone protects the endometrium from hyperplastic changes associated with oestrogen-only therapy.2
Impact on endometrial protection
Postmenopausal estrogen/progestin interventions (PEPI) trial
Study design3
Effects of HRT on endometrial histology in postmenopausal women. The PEPI trial was a 3-year multicentre, randomised, double-blind, placebo-controlled trial. Postmenopausal women (N=596) with no contraindications to HRT were enrolled into the study.
The objective of the study was to report the histological findings of the endometrium of postmenopausal women who were randomised to receive placebo, oestrogen only, or one of three oestrogen plus progestin 28-day regimens:
Study population and eligibility criteria3
The study enrolled a total of 875 healthy postmenopausal women, aged 45 to 64 years at the time of enrolment, representing a diverse racial background. Of these, 596 participants had an intact uterus, while 279 had undergone hysterectomy. All participants provided written informed consent prior to inclusion in the trial.
This analysis focuses on the 596 women with a uterus who were randomly assigned to treatment groups. Detailed demographic and baseline characteristics of the full cohort have been reported previously.
Key inclusion criteria included:
Endpoints3
Histology of endometrium collected at baseline, annual or unscheduled visits by biopsy, curettage, or hysterectomy.
Outcomes3
Women administered oestrogen alone were more likely to develop hyperplasia than those given placebo (27.7% vs 0.8% for simple hyperplasia, 22.7% vs 0.8% for complex hyperplasia, and 11.8% vs 0% for atypical hyperplasia). Women administered oestrogen + progestin had similar rates of hyperplasia as those given placebo (p=0.16).
Effects of HRT on endometrial histology in postmenopausal women. The PEPI trial was a 3-year multicentre, randomised, double-blind, placebo-controlled trial. Postmenopausal women (N=596) with no contraindications to HRT were enrolled into the study.
The objective of the study was to report the histological findings of the endometrium of postmenopausal women who were randomised to receive placebo, oestrogen only, or one of three oestrogen plus progestin 28-day regimens:
- Placebo
- 0.625 mg/d of conjugated equine estrogens (CEEs) only
- CEE + 10 mg medroxyprogesterone acetate (MPA) for the first 12 days
- CEE + 2.5 mg MPA (continuous)
- CEE + 200 mg micronised progesterone for 12 days
Study population and eligibility criteria3
The study enrolled a total of 875 healthy postmenopausal women, aged 45 to 64 years at the time of enrolment, representing a diverse racial background. Of these, 596 participants had an intact uterus, while 279 had undergone hysterectomy. All participants provided written informed consent prior to inclusion in the trial.
This analysis focuses on the 596 women with a uterus who were randomly assigned to treatment groups. Detailed demographic and baseline characteristics of the full cohort have been reported previously.
Key inclusion criteria included:
- Natural menopause occurring between 1 and 10 years prior to enrolment
- Serum follicle-stimulating hormone (FSH) level ≥ 40 IU/L
- Baseline endometrial biopsy showing normal or atrophic histology
- History of breast or endometrial cancer
- Any malignancy (excluding nonmelanoma skin cancer) diagnosed within 5 years prior to baseline
- Serious medical conditions or severe menopausal symptoms
Endpoints3
Histology of endometrium collected at baseline, annual or unscheduled visits by biopsy, curettage, or hysterectomy.
Outcomes3
Women administered oestrogen alone were more likely to develop hyperplasia than those given placebo (27.7% vs 0.8% for simple hyperplasia, 22.7% vs 0.8% for complex hyperplasia, and 11.8% vs 0% for atypical hyperplasia). Women administered oestrogen + progestin had similar rates of hyperplasia as those given placebo (p=0.16).
Endometrial biopsy changes since baseline*4
Treatment regimen
| Result | Placebo | CEE only | CEE + MPA (cyclical) | CEE + MPA (continuous) | CEE + MP | Total no. (%) |
|---|---|---|---|---|---|---|
| Normal† | 116 | 45 | 112 | 119 | 114 | 506 (84.9) |
| Simple (cyclic) hyperplasia‡ | 1 | 33 | 4 | 1 | 5 | 44 (7.4) |
| Complex (adenomatous) hyperplasia‡ | 1 | 27 | 2 | 0 | 0 | 30 (5.0) |
| Atypia‡ | 0 | 14 | 0 | 0 | 1 | 15 (2.5) |
| Adenocarcinoma | 1 | 0 | 0 | 0 | 0 | 1 (0.2) |
| TOTAL | 119 | 119 | 118 | 120 | 120 | 596 (100) |
Normal†
Simple (cyclic) hyperplasia‡
Placebo1
CEE only33
CEE + MPA (cyclical)4
CEE + MPA (continuous)1
CEE + MP5
Total no. (%)44 (7.4)
Complex (adenomatous) hyperplasia‡
Placebo1
CEE only27
CEE + MPA (cyclical)2
CEE + MPA (continuous)0
CEE + MP0
Total no. (%)30 (5.0)
Atypia‡
Placebo0
CEE only14
CEE + MPA (cyclical)0
CEE + MPA (continuous)0
CEE + MP1
Total no. (%)15 (2.5)
Adenocarcinoma
Placebo1
CEE only0
CEE + MPA (cyclical)0
CEE + MPA (continuous)0
CEE + MP0
Total no. (%)1 (0.2)
TOTAL
Placebo119
CEE only119
CEE + MPA (cyclical)118
CEE + MPA (continuous)120
CEE + MP120
Total no. (%)596 (100)
Adapted from Lindenfeld 2002 et al. Data on endometrial histology outcomes across treatment arms. *Includes 30 cases in which the diagnosis was assigned by the local gynaecologist because the local, central and artbiter pathologists gave different options.
†P=.16 (normal vs abnormal) for placebo compared with CEE + MPA (cyc), CEE + MPA (con), and CEE + MP. ‡P<.001 for placebo compared with CEE only.
Study results summary3
The PEPI trial found that postmenopausal women receiving CEE combined with cyclic micronised progesterone experienced the lowest rates of bleeding among all hormone therapy regimens studied. This combination led to fewer bleeding episodes, shorter duration, and reduced bleeding volume over a 3-year period, compared to regimens using MPA.
Notably, 23% of women on CEE + continuous MPA experienced excess bleeding within the first 6 months. In contrast, bleeding was minimal in the placebo and CEE-alone groups. These findings support the use of cyclic micronised progesterone as a more favourable option for managing bleeding in HRT.
Notably, 23% of women on CEE + continuous MPA experienced excess bleeding within the first 6 months. In contrast, bleeding was minimal in the placebo and CEE-alone groups. These findings support the use of cyclic micronised progesterone as a more favourable option for managing bleeding in HRT.
Impact on bleeding patterns4
Subgroup analysis: Lindenfeld 2002 et al. of the PEPI trial demonstrated significantly (P-Value P < 0.05) reduced bleeding in patients receiving oestrogen with cyclical micronised progesterone (n=120) vs those receiving oestrogen with MPA (n=118).4
Objectives: The Lindenfeld study explored whether a significant difference existed bleeding patterns with common regimes of hormone replacement therapy using two different progestogens.4
Methods: In the Lindenfeld trial, bleeding days, volume (pad usage), and episodes were recorded in participant diaries and analysed every 6 months over 3 years. For women on continuous regimens, any bleeding was classified as excess. For cyclical regimens, more than six bleeding episodes per 6-month period was considered excess bleeding.4
Treatment Arms & Participant information: Please see PEPI trial study details above.
Compliance & Monitoring:4
Run-in phase ensured ≥80% medication adherence and absence of bleeding Bleeding (days and pad usage) tracked every 6 months for compliant participants
Safety Information: No specific safety concerns were highlighted in this analysis. However, participants were screened to exclude those with serious illness or cancer history, and safety monitoring was conducted throughout the study.4
Objectives: The Lindenfeld study explored whether a significant difference existed bleeding patterns with common regimes of hormone replacement therapy using two different progestogens.4
Methods: In the Lindenfeld trial, bleeding days, volume (pad usage), and episodes were recorded in participant diaries and analysed every 6 months over 3 years. For women on continuous regimens, any bleeding was classified as excess. For cyclical regimens, more than six bleeding episodes per 6-month period was considered excess bleeding.4
Treatment Arms & Participant information: Please see PEPI trial study details above.
Compliance & Monitoring:4
Run-in phase ensured ≥80% medication adherence and absence of bleeding Bleeding (days and pad usage) tracked every 6 months for compliant participants
Safety Information: No specific safety concerns were highlighted in this analysis. However, participants were screened to exclude those with serious illness or cancer history, and safety monitoring was conducted throughout the study.4
Length and episodes of bleeding by treatment for women with at least 80% adherence3
| Cumulative bleeding | Placebo | CEE | CEE + MPA continuous | CEE + MPA cyclical | CEE + MP cyclical |
|---|---|---|---|---|---|
| Mean length (d) | 1.7 (4.3)* | 51.9 (86.1)* | 99.1 (151.9) | 164.2 (85.0) | 126.2 (86.0) |
| Absolute length (d) | 143 | 2180 | 9315 | 14,777 | 10,979 |
| Mean episodes (n) | 0.3 (0.8)* | 7.2 (9.7)* | 14.2 (16.5)* | 28.8 (11.3) | 23.5 (13.4) |
| Absolute episode (n) | 29 | 303 | 1338 | 2596 | 2044 |
Mean length (d)
Placebo1.7 (4.3)*
CEE51.9 (86.1)*
CEE + MPA cyclical164.2 (85.0)
CEE + MPA continuous99.1 (151.9)
CEE + MP cyclical126.2 (86.0)
Absolute length (d)
Placebo143
CEE2180
CEE + MPA cyclical14,777
CEE + MPA continuous9315
CEE + MP cyclical10,979
Mean episodes (n)
Placebo0.3 (0.8)*
CEE7.2 (9.7)*
CEE + MPA cyclical28.8 (11.3)
CEE + MPA continuous14.2 (16.5)*
CEE + MP cyclical23.5 (13.4)
Absolute episode (n)
Placebo29
CEE303
CEE + MPA cyclical2596
CEE + MPA continuous1338
CEE + MP cyclical2044
Adapted from Lindenfeld 2002 et al. *Contrast with CEE + MP (here and following): P ≤.001.
Study Results Summary: The Lindenfeld trial 2002 et al summarises the results from the Postmenopausal Estrogen and Progestin Interventions Trial demonstrating important differences in bleeding rates between commonly used HRT regimens that offer equivalent endometrial protection. The extent of these differences in bleeding would likely influence continuation rates in clinical practice. In the first 6 months, when side effects and symptoms are most likely to affect continuation, cyclical conjugated equine estrogen plus micronized progesterone was associated with fewer episodes and days of bleeding than conjugated equine estrogen plus either continuous or cyclical medroxyprogesterone acetate.4
Abbreviations
CEE, conjugated equine estrogens; HRT, hormone replacement therapy; MPA, medroxyprogesterone acetate; PEPI, postmenopausal estrogen/progestin interventions.
References
- Data on file. REF-UTO-00078 July 2025
- Utrogestan 100mg (micronised progesterone) Summary of Product Characteristics.
https://www.medicines.org.uk/emc/product/352/smpc.Accessed June 2026 - The Writing Group for the Pepi Trial. JAMA 1996;275(5):370–375
- Lindenfeld EA, et al. Obstet Gynecol 2002;100:853–863.
June 2026 | MAT-PROMO-UTO-0026
Adverse event reporting
Adverse events should be reported. Reporting forms and information can be found at https://yellowcard.mhra.gov.uk/or search for MHRA Yellow Card in the Google Play or Apple App Store. Adverse events should also be reported to Besins Healthcare (UK) Ltd Drug Safety on 0203 862 0920 or Email: drugsafety@besins-healthcare.com
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