Effects of menopausal hormone therapy-based on the role of estrogens, progestogens, and their metabolites in proliferation of breast cancer cells

Yu Deng; Hongyan Jin

doi:10.20892/j.issn.2095-3941.2021.0344

Article Figures & Data

Figures

Tables

Download figure
Open in new tab
Download powerpoint
Figure 1
Signaling pathways of estrogen-mediated breast cancer cell proliferation. Estrogen treatment leads to breast cancer growth through genomic and non-genomic pathways. In the genomic pathway, estrogen and its receptors bind directly to specific DNA sequences called estrogen response elements (EREs) and activate gene expressions; additionally, in non-genomic pathways, estrogen signals can occur by plasma membrane localization of ER, or by GPER, to induce rapid cellular effects by activating several kinase cascades, such as cAMP-PKA, PI3K/AKT, and MEK/ERK 1/2. ER, estrogen receptor; GPER, G protein-coupled estrogen receptor; TF, transcription factor. Adapted from Wilkenfeld et al.³³.
Download figure
Open in new tab
Download powerpoint
Figure 2
Metabolic pathways of E2. There are 3 pathways of E2 metabolism: the 2-hydroxylation pathway, the 4-hydroxylation pathway, and the 16-hydroxylation pathway, of which the 2-hydroxylation pathway is the main metabolic pathway for E2. 2-OH E2, 2-hydroxyestradiol; COMT, catechol-O-methyltransferase; 4-OH E2, 4-hydroxyestradiol; 16α-OH E1, 16α-hydroxyestrone; E2-2,3-Q, E2-2,3-quinone; E2-3,4-Q, E2-3,4-quinone; ROS, reactive oxygen species.
Download figure
Open in new tab
Download powerpoint
Figure 3
Signaling pathways of progestogens leading to breast cancer growth by genomic and non-genomic pathways. In the genomic pathway, progestogens and progesterone receptors (PRs) bind directly to progesterone response elements (PREs) or other DNA-binding transcription factors to promote gene expressions. Rapid progestogenic effects can be induced by non-genomic pathways, in which progestogens (progesterone, medroxyprogesterone acetate, and norethindrone) through some receptors, such as PRs (A), progesterone membrane receptors (B), and progesterone receptor membrane component 1 (C), activate secondary messenger cascades and regulate gene transcription.
Download figure
Open in new tab
Download powerpoint
Figure 4
Metabolic pathways of progesterone (A) and medroxyprogesterone acetate (MPA) (B). A: Progesterone can be reduced to 5α-pregnane-3,20-dione (5αP) by 5α-reductase, or be converted to 3αHP by 3α-hydroxysteroid oxidoreductase (3α-HSO), or be metabolized to 20αHP through 20α-HSO in breast cells. The 5αP promotes breast cancer cell proliferation and inhibits breast cancer cell apoptosis, while 3αHP does the opposite. Abbreviations: 3α-HSO, 3α-hydroxysteroid oxidoreductase; 20α-HSO, 20α-hydroxysteroid oxidoreductase. B: the metabolic pathways of MPA in human liver microsomes.
Download figure
Open in new tab
Download powerpoint
Figure 5
Possible mechanism of genotoxicity of synthetic progestins. The presence of the double bond between carbon 6 and carbon 7 might be significant for genotoxicity. Figure adapted from Siddique et al.¹¹².

Tables

Figures

View popup

Table 1

Classification of estrogens and progestogens

Drug	Classification by structure		Example
Estrogens	Natural estrogen		Estradiol valerate; estradiol (E2)
	Synthetic estrogen		Nylestriol; ethinylestradiol
Progestogens	Natural progestogen		Progesterone (P4)
	Progestins	Retroprogesterone	Dydrogesterone
		17-OH progesterone derivatives (pregnanes)	Medroxyprogesterone acetate (MPA); megestrol acetate; chlormadinone acetate
		17-OH norprogesterone derivatives (norpregnanes)	Gestonorone caproate; nomegestrol acetate
		19-nortestosterone derivatives (estranes)	Norethindrone (NET); norethindrone acetate; lynestrenol; ethinodiol acetate
		19-nortestosterone derivatives (gonanes)	Norgestrel; levonorgestrel; desogestrel; etenogestrel
		19-norprogesterone derivatives (norpregnanes)	Demegestone; promegestone; nesterone; trimegestone
		Spironolactone derivative	Drospirenone

According to reference^5–7.

View popup

Table 2

Results of the clinical studies of menopausal hormone therapy and the risks of breast cancer

Study	Year	Design	Population, n	Mean age (range)	Medications	Follow-up years (mean, range)	HR (95% CI)	RR (95% CI)	OR (95% CI)
Rossouw et al.⁹, WHI^†	2002	RCT	16,608	63.2 (50–79)	EPT (CEE 0.625 mg + MPA 2.5 mg)	5.2 (3.5–8.5)	1.26 (1.00–1.59)	NA	NA
Anderson et al.¹⁹, WHI	2004	RCT	10,739	63.6 (50–79)	ET (CEE 0.625 mg)	6.8 (5.7–10.7)	0.77 (0.59–1.01)	NA	NA
LaCroix et al.²⁰, WHI	2011	RCT	10,739	63.6 (50–79)	ET (CEE 0.625 mg)	10.7	0.77 (0.62–0.95)	NA	NA
Manson et al.²¹, WHI	2013	RCT	10,739 16,608	63.6 (50–79) 63.2 (50–79)	ET (CEE 0.625 mg) EPT (CEE 0.625 mg + MPA 2.5 mg)	13.0 (IQR, 9.1–14.1) 13.2 (IQR, 10.5–14.2)	0.79 (0.65–0.97) 1.28 (1.11–1.48)	NA	NA
Manson et al.²², WHI	2017	RCT	10,739 16,608	63.6 (50–79) 63.2 (50–79)	ET (CEE 0.625 mg) EPT (CEE 0.625 mg + MPA 2.5 mg)	18	0.55 (0.33–0.92) 1.44 (0.97–2.15)	NA	NA
Schierbeck et al.²³, DOPS^†	2012	RCT	1,006	49.5 (45–58)	ET (E2 2 mg)/EPT (E2 2 mg + norethisterone acetate 1 mg)	10 16	0.58 (0.27–1.27) 0.90 (0.52–1.57)	NA	NA
Beral et al.¹⁰, MWS^†	2003	OCS	1,084,110	55.9 (50–64)	ET EPT Tibolone	2.6	NA	1.30 (1.21–1.40) 2.00 (1.88–2.12) 1.45 (1.25–1.68)	NA
Fournier et al.¹¹, EPIC-E3N^†	2005	OCS	54,548	52.8 (40–66.1)	ET EPT (estrogen + progesterone) EPT (estrogen + synthetic progestins)	5.8 (0.1–10.6)	NA	1.1 (0.8–1.6) 0.9 (0.7–1.2) 1.4 (1.2–1.7)	NA
Fournier et al.¹², E3N^†	2008	OCS	80,377	53.1 (40–66.1)	ET EPT (estrogen+ progesterone) EPT (estrogen+ dydrogesterone) EPT (estrogen+ other progestogens)	8.1(2–12)	NA	1.29 (1.02–1.65) 1.00 (0.83–1.22) 1.16 (0.94–1.43) 1.69 (1.50–1.91)	NA
Bakken et al.²⁴, EPIC^†	2011	OCS	133,744	58.1 (52.1–61.5)	ET EPT	8.6	NA	1.42 (1.23–1.64) 1.77 (1.40–2.24)	NA
Fournier et al.²⁵, EPIC-E3N	2014	OCS	78,353	50.2	ET Current use Past use EPT(Estrogen + progesterone/dydrogesterone) Current use Past use EPT (Estrogen + other progestogen^†) Current use Past use	11.2	1.17 (0.99–1.38) 1.06 (0.95–1.19) 1.22 (1.11–1.35) 0.96 (0.87–1.06) 1.87 (1.71–2.04) 1.12 (1.02–1.23)	NA	NA
Holm et al.²⁶, Diet, Cancer and Health Cohort	2019	OCS	29,243	56 (50–64)	ET EPT, sequential regimens EPT, continuous regimens	17	1.37 (0.95–1.98) 1.27 (0.88–1.83) 1.56 (1.05–2.31)	NA	NA
Vinogradova et al.²⁷	2020	OCS	556,109	About 63.3(50–79)	ET Recent users (< 5 years) with longterm use (≥ 5 years) EPT Recent users (< 5 years) with longterm use (≥ 5 years)	20	NA	NA	1.06 (1.03–1.10) 1.15 (1.09–1.21) 1.26 (1.24–1.29) 1.79 (1.73–1.85)

For convenience, we denoted estrogen treatment as ET and estrogen plus progestogens treatment as EPT. RCT, randomized controlled trial; OCS, observational cohort study; WHI, The Women’s Health Initiative; MWS, Million Women Study; EPIC, European Prospective Investigation into Cancer and Nutrition; E3N, Etude Epidémiologique de femmes de la Mutuelle Générale de l’Education Nationale; DOPS, Danish Osteoporosis Prevention Study; Other progestogen^†: chlormadinone acetate, demegestone, dienogest, drospirenone, ethynodiol acetate, gestodene, levonorgestrel, lynestrenol, medrogestone, medroxyprogesterone acetate, megestrol acetate, nomegestrol acetate, norethisterone acetate, and promegestone. HR, Hazard ratio; RR, relative risk; OR, odds ratio.