Evidence on the use of progesterone in menopausal hormone therapy

Figures & data

Table 1. Risk of breast cancer and venous thromboembolism with hormone therapy containing progesterone or progestins in large observational studies.

Study	Estrogen and/or progestogen	Hazard ratio (95% confidence interval)
Breast cancer
Fournier et al., 2005^65	Estrogen alone	1.1 (0.8–1.6)
	Estrogen plus progesterone	0.9 (0.7–1.2)
	transdermal estrogen	0.9 (0.7–1.2)
	oral estrogen	No events
	Estrogen plus synthetic progestins	1.4 (1.2–1.7)
	transdermal estrogen	1.4 (1.2–1.7)
	oral estrogen	1.5 (1.1–1.9)
Fournier et al., 2008^66	Oral estrogen alone	1.32 (0.76–2.29)
	Oral estrogen plus progestogen
	progesterone	Not analyzed^a
	dydrogesterone	0.77 (0.36–1.62)
	medrogestone	2.74 (1.42–5.29)
	chlormadinone acetate	2.02 (1.00–4.06)
	cyproterone acetate	2.57 (1.81–3.65)
	promegestone	1.62 (0.94–2.82)
	nomegestrol acetate	1.10 (0.55–2.21)
	norethisterone acetate	2.11 (1.56–2.86)
	medroxyprogesterone acetate	1.48 (1.02–2.16)
	Transdermal estrogen alone	1.28 (0.98–1.69)
	Transdermal estrogen plus progestogen
	progesterone	1.08 (0.89–1.31)
	dydrogesterone	1.18 (0.95–1.48)
	medrogestone	2.03 (1.39–2.97)
	chlormadinone acetate	1.48 (1.05–2.09)
	cyproterone acetate	Not analyzed^a
	promegestone	1.52 (1.19–1.96)
	nomegestrol acetate	1.60 (1.28–2.01)
	norethisterone acetate	Not analyzed^a
	medroxyprogesterone acetate	Not analyzed^a
Fournier et al., 2014^64	Estrogen alone	1.17 (0.99–1.38)
	Estrogen plus progesterone/dydrogesterone	1.22 (1.11–1.35)
	Estrogen plus synthetic progestins	1.87 (1.71–2.04)
Cordina-Duverger et al., 2013^55	Estrogen alone (any)	1.19 (0.69–2.04)
	Estrogen (any) with progestogens	1.33 (0.92–1.92)
	natural progesterone	0.80 (0.44–1.43)
	synthetic progestins	1.72 (1.11–2.65)
	progesterone derivatives	1.57 (0.99–2.49)
	testosterone derivatives	3.35 (1.07–10.4)
Venous thromboembolism
Canonico et al., 2010^3	Oral estrogens	1.7 (1.1–2.8)
	Transdermal estrogens	1.1 (0.8–1.8)
	Any estrogen with progestogens
	progesterone	0.9 (0.6–1.5)
	pregnane derivatives	1.3 (0.9–2.0)
	nortestosterone derivatives	1.4 (0.7–2.4)
	norpregnane derivatives	1.8 (1.2–2.7)
Canonico et al., 2007^4	Oral estrogens	4.2 (1.5–11.6)
	Transdermal estrogens	0.9 (0.4–2.1)
	Any estrogen with progestogens
	progesterone	0.7 (0.3–1.9)
	pregnane derivatives	0.9 (0.4–2.3)
	norpregnane derivatives	3.9 (1.5–10.0)
Olie et al., 2011 (recurrent)^5	Oral estrogens	6.4 (1.5–27.3)
	Transdermal estrogens ± progestogens	1.0 (0.4–2.4)
	estrogen alone	1.1 (0.2–8.1)
	progesterone	1.0 (0.3–3.2)
	Norpregnane derivatives	4.7 (1.1–20.0)
	pregnane derivatives	No events
Ischemic stroke
Canonico et al., 2016^6	Oral estradiol	1.58 (1.01–2.49)
	Transdermal estradiol	0.83 (0.56–1.24)
	Estradiol with progestogens
	progesterone	0.78 (0.49–1.26)
	pregnane derivatives	1.00 (0.60–1.66)
	nortestosterone derivatives	1.26 (0.62–2.58)
	norpregnane derivatives	2.25 (1.05–4.81)

^a Not analyzed, less than five cases of breast cancer.

Table 2. Risk of breast cancer with hormone therapy containing progesterone or progestins by duration of use in large observational studies.

Study	Estrogen and/or progestogen	Hazard ratio (95% confidence interval)
Fournier et al., 2005^65	Transdermal estrogens plus progesterone
	<2 years	0.9 (0.6–1.4)
	2–4 years	0.7 (0.4–1.2)
	≥4 years	1.2 (0.7–2.0)
	Transdermal estrogens plus synthetic progestins
	<2 years	1.6 (1.3–2.0)
	2–4 years	1.4 (1.0–1.8)
	≥4 years	1.2 (0.8–1.7)
	Oral estrogens plus synthetic progestins^a
	<2 years	1.2 (0.9–1.8)
	2–4 years	1.6 (1.1–2.3)
	≥4 years	1.9 (1.2–3.2)
Fournier et al., 2008^66	Estrogens plus progesterone
	<2 years	0.71 (0.44–1.14)
	2–4 years	0.95 (0.67–1.36)
	4–6 years	1.26 (0.87–1.82)
	≥6 years	1.22 (0.89–1.67)
	Estrogens plus dydrogesterone
	<2 years	0.84 (0.51–1.38)
	2–4 years	1.16 (0.79–1.71)
	4–6 years	1.28 (0.83–1.99)
	≥6 years	1.32 (0.93–1.86)
	Estrogens plus other progestogens
	<2 years	1.36 (1.07–1.72)
	2–4 years	1.59 (1.30–1.94)
	4–6 years	1.79 (1.44–2.23)
	≥6 years	1.95 (1.62–2.35)
Fournier et al., 2014^64	Estrogens plus progesterone/dydrogesterone
	≤5 years	1.13 (0.99–1.29)
	>5 years	1.31 (1.15–1.48)
	Estrogens plus other progestogens
	≤5 years	1.70 (1.50–1.91)
	>5 years	2.02 (1.81–2.26)

^a Oral estrogens with progesterone not analyzed due to low number of women who took it.

Fournier A, Berrino F, Riboli E, Avenel V, Clavel-Chapelon F. Breast cancer risk in relation to different types of hormone replacement therapy in the E3N-EPIC cohort. Int J Cancer 2005;114:448–54

 PubMed Web of Science ®Google Scholar

Fournier A, Berrino F, Clavel-Chapelon F. Unequal risks for breast cancer associated with different hormone replacement therapies: results from the E3N cohort study. Breast Cancer Res Treat 2008;107:103–11

 PubMed Web of Science ®Google Scholar

Fournier A, Mesrine S, Dossus L, Boutron-Ruault MC, Clavel-Chapelon F, Chabbert-Buffet N. Risk of breast cancer after stopping menopausal hormone therapy in the E3N cohort. Breast Cancer Res Treat 2014;145:535–43

 PubMed Web of Science ®Google Scholar

Riis BJ, Thomsen K, Strom V, Christiansen C. The effect of percutaneous estradiol and natural progesterone on postmenopausal bone loss. Am J Obstet Gynecol 1987;156:61–5

 PubMed Web of Science ®Google Scholar

Canonico M, Fournier A, Carcaillon L, et al. Postmenopausal hormone therapy and risk of idiopathic venous thromboembolism: results from the E3N cohort study. Arterioscler Thromb Vasc Biol 2010;30:340–5

 PubMed Web of Science ®Google Scholar

Canonico M, Oger E, Plu-Bureau G, et al. Hormone therapy and venous thromboembolism among postmenopausal women: impact of the route of estrogen administration and progestogens: the ESTHER study. Circulation 2007;115:840–5

 PubMed Web of Science ®Google Scholar

Olie V, Plu-Bureau G, Conard J, Horellou MH, Canonico M, Scarabin PY. Hormone therapy and recurrence of venous thromboembolism among postmenopausal women. Menopause 2011;18:488–93

 PubMed Web of Science ®Google Scholar

Canonico M, Carcaillon L, Plu-Bureau G, et al. Postmenopausal hormone therapy and risk of stroke: impact of the route of estrogen administration and type of progestogen. Stroke 2016;47:1734–41

 PubMed Web of Science ®Google Scholar