Study

First author, year

Appropriate and clearly focused question?

Yes/no/unclear

Comprehensive and systematic literature search?

Yes/no/unclear

Description of included and excluded studies?

Yes/no/unclear

Description of relevant characteristics of included studies?

Yes/no/unclear

Appropriate adjustment for potential confounders in observational studies?

Yes/no/unclear/not applicable

Assessment of scientific quality of included studies?

Yes/no/unclear

Enough similarities between studies to make combining them reasonable?

Yes/no/unclear

Potential risk of publication bias taken into account?

Yes/no/unclear

Potential conflicts of interest reported?

Yes/no/unclear

Asi et al. 2016 ("ACOG Committee Opinion No. 420, November 2008: hormone therapy and heart disease," 2008)

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Sjogren et al. 2016 (Sjogren et al., 2016)

Yes

Yes

Yes

Yes

Yes

Yes

Not applicable

Yes

Yes

Study reference

(first author, year of publication)

Bias due to a non-representative or ill-defined sample of patients?

(unlikely/likely/unclear)

Bias due to insufficiently long, or incomplete follow-up, or differences in follow-up between treatment groups?

(unlikely/likely/unclear)

Bias due to ill-defined or inadequately measured outcome ?

(unlikely/likely/unclear)

Bias due to inadequate adjustment for all important prognostic factors?

(unlikely/likely/unclear)

Fournier 2008 (Fournier, Fabre, et al., 2008)

Unlikely (The exposed cohort was somehow representative, the non-exposed cohort was drawn from the same community)

Unlikely (adequacy of follow-up cohort)

Unlikely (self-report questionnaires of files of health insurance plan, pathology reports were obtained in 96% of cases)

Unclear

Espie 2007 (Espie et al., 2007)

Unlikely (The exposed cohort was somehow representative, the non-exposed cohort was drawn from the same community)

Unlikely (adequacy of follow-up cohort)

Likely (no co description of assessment of outcome)

Unclear

Cordina – Duverger 2013 (Cordina-Duverger et al., 2013)

Unlikely (The exposed cohort was somehow representative, the non-exposed cohort was drawn from the general population within predefined quotas by age and socio-economic status (SES).)

Unclear

Likely (The statistical analysis was based on small sample sizes. The primary endpoint important for power calculation was not given)

Likely (Dosage and route of administration

of progesterone were not assessed).

Study reference

Study characteristics

Patient characteristics

Intervention (I)

Comparison / control (C)

Follow-up

Outcome measures and effect size

Comments

Asi 2016 (Asi et al., 2016)

SR and meta-analysis of cohort and case-control studies

Literature search up to May 2016

A: Espie 2007

B: Fournier 2008

C: Cordina-Duverger 2013

Study design:

A: Cohort

B: Cohort

C: Case-control

Setting and Country:

A: France

B: France

C: France

Source of funding:

Non-commercial

Inclusion criteria SR: women aged 45 – 59 years within 1- years of menopause, using MHT (comparing estrogen + progesterone with estrogen +synthetic progestins), >6 months follow-up period

Exclusion criteria SR: not described

3 studies included

N

A 4949 women

B: 80.377 women

C: 1555 women

A: Estradiol + natural progesterone

B: Estrogen + progesterone

C: Estrogen + progesterone

A: Estradiol + synthetic progestins (excluding medroxyprogesterone acetate and 19-nortestosterone derivatives)

B: Estrogen + synthetic progestins (alsmost exclusively estradiol compounds)

C: Estrogen + synthetic progestins

End-point of follow-up:

A: 2.4 years

B: 8.1 years

C: 4 years

Outcome measure-1

Defined as breast cancer

A: Breast cancer incidence

Estradiol + progesterone

0.40% (4/999)

Estradiol + synthetic progestin 0.94% (12/1272)

RR 0.42 (95% CI 0.13 – 1.31)

B: Breast cancer incidence

Estradiol + progesterone

0.40% (4/999)

Estradiol + synthetic progestin 0.94% (12/1272)

Breast cancer risk (RR)

RR 0.67 (95% CI 0.76 – 0.81)

C: Breast cancer risk

Estrogen + progesterone

OR 0.80 [95% CI 0.44-1.43]

Estradiol + synthetic progestin

OR 1.72 [95% CI 1.11-2.65]

Conclusion:

Observation studies suggest that estrogen and progesterone use may be associated with lower breast cancer risk compared to synthetic progestin.

Only low-risk women are included in these studies, since common practice in France is to avoid prescribing MHT to high-risk women.

Study reference

Study characteristics

Patient characteristics ²

Intervention (I)

Comparison / control (C) ³

Follow-up

Outcome measures and effect size ⁴

Comments

Fournier 2008 (Fournier, Berrino, et al., 2008)

Type of study

Prospective cohort study

Setting

Women, living in metropolitan France and insured by the Mutuelle Générale de l’ Education Nationale

Country
France

Source of funding

Financial support of the “Mutuelle Générale de l’Education Nationale” (MGEN); European Community; French League against Cancer (LNCC); Gustave Roussy Institute (IGR); French Institute of Health and Medical Research (Inserm); 3M Company.

Inclusion criteria:

Postmenopausal women

Exclusion criteria:

A cancer other than a basal cell carcinoma, no age at first HRT use available

N total at baseline:

Cases: 2,265

Control: 78,112

Important prognostic factors:

Age (mean) + SD

55.0 ±4.8 for MHT never-users, 52.3 ± 4.1 for MHT ever-users

Estrogen + progesterone (almost exclusively estradiol compounds)

Estrogen + synthetic progestins (almost exclusively estradiol compounds)

Length of follow-up:

Mean duration 8.1 postmenopausal years

Loss to follow-up

The last follow-up questionnaire was completed by 88.7% of the 80,377 women;

Reasons of incomplete data

of the 9,095 non-respondents, 892 had been diagnosed with a cancer, 866 had died, and 7,337 were lost to follow-up (of them, 3,979 had replied to the previous questionnaire).

Outcome measures and effect size (include 95%CI and p-value if available):

The association of estrogen-progestagen combinations with breast cancer risk varied significantly according to the type of progestagen: the relative risk was 1.00 (0.83-1.22) for estrogen-progesterone, 1.16 (0.94-1.43) for estrogen-dydrogesterone, and 1.69 (1.50-1.91) for estrogen combined with other progestagens. This latter category involves progestins with different physiologic activities (androgenic, nonandrogenic, antiandrogenic), but their associations with breast cancer risk did not differ significantly from one another.

Espié 2007 (Espie et al., 2007)

Type of study

Prospective observational study

The MISSION Study (Menopause: Risk of Breast Cancer, Morbidity and Prevalence)

Setting

Multiple centre study

Country

France

Source of fundingResearch

support from THERAMEX Laboratories, a subsidiary

of theMerck Serono group.

Inclusion criteria:

Women on HRT

Natural progesterone, a progesterone-like compound, a pregnane derivative or a norpregnane derivative

Exclusion criteria:

19-nortestosterone derivatives, formulations containing medroxyprogesterone acetate

N total at baseline:

Cases: 2693 women

Control: 2256 women

Important prognostic factors:

Female age

I: 60.6 ± 6.3 years

C: 64.2 ± 8.3 years

Women on HRT regimens commonly prescribed in France or who had stopped < or =5 years previously.

Women who had never received HRT or stopped >5 years previously

Length of follow-up:

Mean duration 2,5 postmenopausal years

Loss to follow-up:

1806 (26.7%) of patients, no case report form was obtained.

Reasons of incomplete data

Of these patients, eight died,

195 officially withdrew,

1603 had not returned to gynecologist

or were lost to follow-up

The breast cancer incidence was 0.28% for estradiol alone, 0.40% for estradiol + natural progesterone, and 0.94% for estradiol+ synthetic progestin; there was no statistically

significant difference between the groups.

Cordina-Duverger 2013 (Cordina-Duverger et al., 2013)

Type of study

Case–control study

Setting

Population-based case-control study

in two French administrative

areas (départements) located in Eastern and Western part of

France, respectively.

Country

France

Source of funding

Grants from the French National Institute of Cancer (INCa), Fondation de France, the French Agency for

Environmental and Occupational Health Safety (ANSES – ex-AFSSET), the French National Research Agency (ANR), the League against Cancer (Grand

Ouest).

Inclusion criteria:

Menopausal women

(no menstruation for twelve months or more (natural menopause, bilateral oophorectomy, or if they used MHT before natural

cessation of menstruation

Exclusion criteria:

Women with unknown

menopausal status below 50 years old were excluded from the

analysis.

N total at baseline:

Cases: 739women

Control: 816 women

Important prognostic factors:

Female age

Range (25 – 75 years)

The case group included incident cases of in situ or invasive

breast cancer, women aged 25-75.

The control group included women from the general population within predefined quotas by age and socio-economic status (SES).

Length of follow-up:

Mean duration 4 years

Loss to follow-up:

Unclear?

Compared to never MHT use, current use of EPT containing a synthetic progestogen for 4 or more years was associated with a significantly increased BC risk (adjusted OR 2.07; 95 % CI 1.26–3.39), but EPT containing micronized progesterone was not (adjusted OR 0.79; 95 % CI 0.37–1.71).

The statistical analysis was based on small sample

sizes. The primary endpoint important for power

calculation was not given.

Dosage and route of administration

of progesterone were not assessed.

Study reference

(first author, year of publication)

Bias due to a non-representative or ill-defined sample of patients?

(unlikely/likely/unclear)

Bias due to insufficiently long, or incomplete follow-up, or differences in follow-up between treatment groups?

(unlikely/likely/unclear)

Bias due to ill-defined or inadequately measured outcome ?

(unlikely/likely/unclear)

Bias due to inadequate adjustment for all important prognostic factors?

(unlikely/likely/unclear)

Canonico 2016 (Canonico et al., 2016)

Unlikely (The exposed cohort was somehow representative, the non-exposed cohort was drawn from the same community)

Unclear

Unlikely (Clear description outcome measure, series of sensitivity analysis to assess the robustness the findings were performed).

Likely (Incomplete data on risk factors and comorbidities)

Study reference

Study characteristics

Patient characteristics²

Intervention (I)

Comparison / control (C)

Follow-up

Outcome measures and effect size ⁴

Comments

Canonico 2016 (Canonico et al., 2016)

Type of study

Nested case-control study

Setting

Participants were identified using the French National Health Insurance database and French National hospital data

Country

France

Source of funding

The study was supported by National Institute of Health and Medical Research (INSERM) and Institute of Research in Public Health (IReSP) in France

Inclusion criteria:

French women first hospitalization for a stroke aged 51 to 62 years

Exclusion criteria: Excluded cases identified

in aftercare and rehabilitation units or home hospitalization,

contraindication to HT use, personal history of cardiovascular disease or gynecological

cancers (breast, uterine, ovary), cases using antithrombotic

N total at baseline:

Cases: 3144 Controls: 12 158

Important prognostic factors:

Female age

I: 56.7 ± 2.8 years

C: 56.6 ± 2.7years

HT users were classified according to route of estrogen administration (oral or transdermal) and type of concomitant progestogen (progesterone, pregnane derivatives, norpregnane derivatives, and nortestosterone derivatives).

Controls were randomly selected among healthy women who had never been hospitalized during the follow-up and who had no contraindication to HT use

Follow-up

Covers 3 consecutive years

Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (95% CI)

There was no association of IS with use of progesterone (OR, 0.78; 95% CI, 0.49-1.26), pregnanes (OR, 1.00; 95% CI, 0.60-1.67) and nortestosterones (OR, 1.26; 95% CI, 0.62-2.58), whereas norpregnanes increased IS risk (OR, 2.25; 95% CI, 1.05-4.81).

Incomplete data on risk factors and comorbidities

Study reference

(first author, year of publication)

Bias due to a non-representative or ill-defined sample of patients?¹

(unlikely/likely/unclear)

Bias due to insufficiently long, or incomplete follow-up, or differences in follow-up between treatment groups?²

(unlikely/likely/unclear)

Bias due to ill-defined or inadequately measured outcome ?³

(unlikely/likely/unclear)

Bias due to inadequate adjustment for all important prognostic factors?⁴

(unlikely/likely/unclear)

Canonico 2007 (Canonico et al., 2007)

Unlikely (The exposed cohort was somehow representative, the non-exposed cohort matched for center, 2-year age band, admission date, and area of residence, matched with 1 to 3 controls)

Unclear

Unlikely (Clear description outcome measure).

Unlikely (adjustment for age, obesity status, familial history of VTE, and varicose veins, education, age at menopause, hysterectomy, and cigarette smoking)

Canonico 2010 (Canonico et al., 2010)

Likely (Women recruited in the E3N study were mostly teachers and could represent a health-conscious population).

Unlikely (adequacy of follow-up cohort)

Likely (HT use was self-reported and nondifferential misclassifications regarding exposure might have occurred during follow-up)

Unlikely (adjustment for for age, body-mass index, parity, education level, and time-period).

Study reference

Study characteristics

Patient characteristics ²

Intervention (I)

Comparison / control (C) ³

Follow-up

Outcome measures and effect size ⁴

Comments

Canonico 2007(Canonico et al., 2007)

Type of study

Case-control study

Setting:

Multicenter study, 8 hospitals and in the general population

Country: France

Source of funding: Multiple foundations in France and by grants from Aventis, Besins International, Sanofi, and Servier Institute

Inclusion criteria:

All women aged 51 to 62 years

with a first hospitalization for a stroke

Exclusion criteria:

A history of VTE, contraindication for hormone therapy (breast cancer, endometrial cancer, and cardiovascular disease), predisposing factor for VTE

N total at baseline:

Cases: 271

Control: 610

Important prognostic factors:

Female age

I: 61.6 ± 6.7 years

C:61.5 ± 6.6 years

Women were classified as users of micronized progesterone or pregnane derivatives, norpregnane derivatives, or nortestosterone derivatives. Pregnane derivatives included dydrogesterone or medrogestone, chlormadinone acetate, cyproterone acetate, or medroxyprogesterone acetate. Norpregnane derivatives included either nomegestrol acetate or promegestone

Controls had to

have been admitted to the hospital with an a priori diagnosis unrelated

to estrogen use (diseases of eye, ear, skin,

respiratory and alimentary tracts, bones and joints, and kidneys; infectious

diseases; and diabetes).

Cases and controls were matched for center, 2-year age band, admission date, and area of residence. Each case was matched

with 1 to 3 controls.

Study period from 1999 - 2006

There was no significant association of VTE with micronized progesterone and pregnane derivatives (OR, 0.7; 95% CI, 0.3 to 1.9 and OR, 0.9; 95% CI, 0.4 to 2.3, respectively). In contrast, norpregnane derivatives were associated with a 4-fold-increased VTE risk (OR, 3.9; 95% CI, 1.5 to 10.0).

Small number of subjects within progestogen subgroups, especially among users of oral estrogen

Canonico 2010 (Canonico et al., 2010)

Prospective cohort study

Setting:

E3N is a prospective cohort initiated in 1990, the aim of which is to investigate risk factors for cancer in women.

Country

French

Source of funding: Financial support of the MGEN, European Community; French League against Cancer, Gustave Roussy Institute, French Institute of Health and Medical Research, 3M Company.

Inclusion criteria:

Postmenopausal women

Exclusion criteria:

Personal history of thrombotic events or cancer before the start of follow-up

N total at baseline:

Cases: 549

Control: 80 308

Important prognostic factors:

At the beginning of follow-up female age 54.0 years, mean body-mass index

22.6 kg/m2.

Progestogens were categorized according to the progestogen North American Menopause Society (NAMS) classification. Women were classified as users of either micronised progesterone, pregnane derivatives, norpregnane derivatives, or nortestosterone derivatives. Pregnane derivatives included dydrogesterone, medrogestone, chlormadinone acetate, cyproterone acetate, and medroxyprogesterone acetate. Norpregnane derivatives included nomegestrol acetate and promegestone. Nortestosterone derivatives were norethisterone acetate

Non-users

Average follow-up: 10.1 years

In the principal analysis, 65 of the validated cases were

excluded because no information on predisposing factors was

available.

The main clinical outcome was a first documented incident episode of pulmonary embolism or lower-extremity deep vein thrombosis having occurred without any of the following predisposing factors (ie, cancer, surgery, immobilization, or trauma).

Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using Cox proportional models. The thrombotic risk significantly differed by concomitant progestogens type (homogeneity: P<0.01): there was no significant association with progesterone, pregnanes, and nortestosterones (HR=0.9; 95% CI: 0.6 to 1.5, HR=1.3; 95% CI: 0.9 to 2.0 and HR=1.4; 95% CI: 0.7 to 2.4). However, norpregnanes were associated with increased thrombotic risk (HR=1.8; 95% CI: 1.2 to 2.7).

Women recruited in the E3N study were mostly teachers and could represent a health-conscious population

Another limitation is that HT use was self-reported and nondifferential misclassifications regarding exposure might have occurred during follow-up

Study reference

Study characteristics

Patient characteristics

Intervention (I)

Comparison / control (C)

Follow-up

Outcome measures and effect size

Comments

Sjögren et al. 2016 (Sjogren et al., 2016)

SR of cohort studies

Literature search up to March 2016

A: Fournier 2014

B: Allen 2010

Study design: cohort [prospective and retrospective]

Setting and Country:

A: France

B: Denmark, France, Germany, Netherlands, Italy, Norway, Spain, United Kingdom

Source of funding:

Non-commercial

Inclusion criteria: Women with an intact uterus being treated with systemic hormone therapy for menopausal symptoms.

Exclusion criteria: Carrier of BRCA1 and 2 genes or if history of current or prior gynecological cancers, breast cancer, hysterectomy or hormonal therapy within one month prior to the beginning of the study.

2 studies included

Important patient characteristics at baseline:

A: 65.630 women

B: 370.000 women

Mean age

A: 64.3 years

B: 57 years, at

diagnosis 65 years

Studies on any combination of unopposed estrogen, continuous and sequential combined estrogen plus progestin compared with placebo or never-users were included. SERM and antiestrogens were not considered. Only oral regimens and treatment lasting at least a year were considered.

A: Hormone therapy

B: Hormone therapy

A: Never users of MHT

B: Never users of MHT

End-point of follow-up:

A: 10.8 years

B: 9.0 years

No complete outcome available:

A: For 9,541 no follow-up was available.

B: Of the 370,000 women incomplete follow-up data (n = 2,296), or no return of the baseline lifestyle questionnaire (n = 509).

Outcome measure

Risk of endometrial cancer

A: Risk of endometrial cancer identified by self-reports.

B: Risk of endometrial cancer assessed by cancer registries, herof 81% verified by histology reports.

Effect measure: Cox proportional hazard ratio [95% CI]

A: Estradiol + progesterone HR 1.96 (95% CI 1.41 – 2.73);

Estradiol + dydrogesterone HR 0.67 (95% CI 0.36 - 1.25); Estradiol + other progesterone derivative HR 0.65 (95% CI 0.41 - 1.02)

B: Estradiol + progesterone HR 2.42 (95% CI 1.53 - 3.83);

Estradiol + Progesterone derivative HR 1.23 (95% CI 0.84 - 1.79); Estradiol + Testosterone derivative HR 1.09 (95% CI 0.74 - 1.61)

Facultative:

For formulations with micronized progesterone, an increased risk with a HR of 1.96 (95% CI 1.41 – 2.73) and 2.42 (95% CI 1.53 – 3.83) was found.

A: Risk of bias: some risk of detection and performance bias, as outcome could not be excluded prior to baseline. GRADING of evidence: Reliable estimate, high external and internal validation high quality of evidence.

B: Risk of bias: Low risk of selection bias. Some risk of detection bias. GRADING of evidence: high internal validity moderate quality of evidence.