Review of menopausal hormone therapy with estradiol and progesterone versus other estrogens and progestins

Figures & data

Figure 1. Study selection follow chart. CEE: conjugated equine estrogens; E2: estradiol; P4: progesterone; QOL: quality of life; VMS: vasomotor symptoms. ^aThree articles reported outcomes with both E2 versus CEE and P4 versus progestins. ^bThirteen articles reported multiple outcomes with P4 versus progestins.

Table 1. Studies comparing endometrial outcomes with E2 versus CEE and P4 versus synthetic progestogens.

Reference	Study design (duration)	Population	Treatment (dose; number of subjects)	Reported outcomes
E2 vs CEE
Ettinger et al. [7]	Prospective randomized study (24 weeks)	87 postmenopausal women aged 45–69 years with a uterus	Unopposed estrogens E2 (0.5 mg; n = 27) E2 (1.0 mg; n = 29) CEE (0.625 mg; n = 31)	Mean weekly endometrial growth 0.5 mg E2: 0.08 ± 0.17 mm/wk (p < .05 vs the other two regimens) 1.0 mg E2: 0.19 ± 0.14 mm/wk 0.625 mg CEE: 0.19 ± 0.15 mm/wk Unscheduled vaginal bleeding (% patient) 0.5 mg E2: 15% (p = .05 vs CEE) 1.0 mg E2: 32% 0.625 mg CEE: 41% Unscheduled bleeding score ≥20 (% patient) 0.5 mg E2: 7% (p = .02 vs CEE) 1.0 mg E2: 14% 0.625 mg CEE: 28%
P4 vs progestin
Writing group for the PEPI trial [51]	Prospective randomized controlled study (3 years)	596 postmenopausal women aged 45–64 years with a uterus	CEE (0.625 mg) plus Cyclic MPA (10 mg; n = 118) Continuous MPA (2.5 mg; n = 120) Cyclic P4 (200 mg; n = 120) CEE alone (0.625 mg; n = 119) Placebo (n = 119) Cyclic progestogens taken on days 1 to 12 of a 28-day cycle	Occurrence of abnormal endometrial biopsy was similar with any combined MHT vs placebo (p = .16), but significantly higher with CEE only vs placebo (p = .001); No endometrial adenocarcinoma occurred with any MHT
Ryan and Rosner [52]	Prospective randomized open-label parallel-group study (9 months)	182 postmenopausal, non-hysterectomized women aged 45–65 years who had been amenorrheic for ≥6 months, and had symptoms of estrogen deficiency	CEE (0.625 mg) plus cyclic P4 (200 mg; n = 89) MPA (5 mg; n = 93) CEE taken on days 1 to 25 of a 30-day cycle, combined with progestogens on days 12 to 25 of the cycle	P4 vs MPA at month 9: Amenorrhea 39% vs 12% (p = .001) Days of bleeding 4.3 vs 6.2 (p = .01) Blood flow scale 0.9 vs 1.4 (p < .001)
Pélissier et al. [53]	Randomized parallel-group study (18 months)	336 postmenopausal amenorrheic women aged ≤57 years with intact uterus	TD E2 (1.5 mg/day) plus cyclic P4 (200 mg; n = 169) CMA (10 mg; n = 167) E2 taken on days 1 to 24 every month, combined with progestogens on days 11 to 24 of the month	P4 vs CMA at month 18: No significant difference in endometrial biopsy results between groups: No endometrial hyperplasia with both MHT; Atrophic, inactive, secretory endometrium: 86.9% vs 96.3%; Proliferative endometrium: 8.3% vs 3.7%; Amenorrhea rate: 37.1% vs 11.9% Irregular bleeding 15.9% vs 7.4% (p = .03)
Jondet et al. [54]	Randomized study (18 months)	336 postmenopausal women	TD E2 (1.5 mg/day) plus cyclic P4 (200 mg; n = 169) CMA (10 mg; n = 167) E2 taken on days 1 to 24 every month, combined with progestogens on days 11 to 24 of the month	P4 vs CMA at month 18: Atrophic endometrium: 27.1% vs 19.5%; Secretory endometrium: 62.5% vs 76.8%; Proliferative endometrium: 8.3% vs 3.7%; Endometrial polyps: 2.1% vs 0%
Cummings and Brizendine [55]	Prospective randomized study (8 weeks)	23 postmenopausal women aged <59 years with amenorrhea for >1 year	2 cycles of 2-week CEE (0.625 mg) followed by 2-week CEE (0.625 mg) plus P4 (200 mg; n = 13) or MPA (5 mg; n = 10)	P4 vs MPA: Smaller magnitude and shorter duration of vaginal bleeding
Di Carlo et al. [56]	Prospective randomized study (1 year)	100 postmenopausal women, 12 to 36 months after spontaneous menopause	TD E2 (50 μg) plus oral, cyclic MPA (10 mg; n = 25) NOMAC (5 mg; n = 25) DYD (10 mg; n = 25) P4 (200 mg; n = 25) Cyclic progestogens taken on days 14 to 25 of a 28-day cycle	P4 vs MPA, NOMAC, DYD: Endometrial thickness significantly increased versus baseline (p < .05), but similar among groups; Amenorrhea episode: 7.5% vs 9.8%, 5.7%, 8.4% (p = NS); Irregular bleeding episode: 12% vs 8.4%, 5.7%, 7.5% (p < .05 P4 vs NOMAC)
Allen et al. [43]	Prospective cohort study (1992–2000)	115,474 postmenopausal, non-hysterectomized women	Combined MHT containing P4 (9.0%) Progesterone derivatives (35.8%) Testosterone derivatives (54.9%)	HR (95% CI) for endometrial cancer (current vs never use): P4: 2.42 (1.53–3.83) Progesterone derivatives: 1.23 (0.84–1.79) Testosterone derivatives: 1.09 (0.74–1.61) Pheterogeneity = .02
Zheng et al. [57]	Prospective randomized study (3 months)	96 early postmenopausal women aged 40–60 years with climacteric symptoms	Oral E2V plus cyclic P4 (n = 32) MPA (n = 32) Cyclic progestogens received on days 19 to 30 of a 30-day cycle	Vaginal bleeding (% patients) P4: 26.7%; MPA: 82.1%
Fournier et al. [44]	Prospective cohort study (1992–2008)	65,630 postmenopausal, non-hysterectomized women aged 40–65 years	In ever users of combined MHT, estrogen plus oral: P4 (40.2%) DYD (28.8%) Progesterone derivative^a (59%) Norsteroid derivative^b (13.5)	HR (95% CI) for endometrial cancer: Ever vs never use P4: 1.80 (1.38–2.34) DYD: 1.05 (0.76–1.45) Progesterone derivative: 0.79 (0.60–1.05) Norsteroid derivative: 1.30 (0.85–1.99) Duration ≤5 years vs never use P4: 1.39 (0.99–1.97) DYD: 0.87 (0.57–1.32) Progesterone derivative: 0.81 (0.59–1.13) Norsteroid derivative: 1.32 (0.81–2.15) Duration >5 years vs never use P4: 2.66 (1.87–3.77) DYD: 1.69 (1.06–2.70) Progesterone derivative: 0.94 (0.62–1.44) Norsteroid derivative: 0.98 (0.31–3.07)
Gao et al. [63]	Prospective randomized controlled study (24 months)	96 early postmenopausal women aged 40–60 years with climacteric symptoms	Oral E2V (1 mg) plus cyclic MPA (4 mg, n = 32) P4 (100 mg, n = 32) Cyclic progestogens taken on days 19 to 30 of a 30-day cycle	Compared with baseline at month 24: Endometrial thickness increased significantly with E2V/P4, but not E2V/MPA; Incidence of endometrial thickness ≥5 mm: E2V/P4: 29.6% E2V/MPA: 18.5% p = NS between groups

CEE: conjugated equine estrogens; CI: confidence interval; CMA: chlormadinone acetate; DYD: dydrogesterone; E2: estradiol; E2V: estradiol valerate; HR: hazard radio; MHT: menopausal hormone therapy; MPA: medroxyprogesterone acetate; NOMAC: nomegestrol acetate; P4: progesterone; PEPI: the Postmenopausal Estrogen/Progestin Interventions study; RR; relative risk; TD: transdermal.

Early postmenopausal: amenorrhea >6 months and <5 years.

^aProgesterone derivative included CMA, cyproterone acetate, demegestone, medrogestone, MPA, NOMAC, or promegestone.

^bNorsteroid derivative included dienogest, drospirenone, ethynodiol, gestodene, levonorgestrel, norethisterone acetate, or lynestrenol.

Table 2. Studies comparing cardiovascular outcomes with E2 versus CEE and P4 versus synthetic progestogens.

Reference	Study design (duration)	Population	Treatment (dose; number of subjects)	Reported outcomes
E2 vs CEE
Lobo et al. [26]	Prospective cross-over study (1 month)	24 non-obese women aged 54.8 ± 1.2 years, weighed 64 ± 2 kg, postmenopausal ≥2 years, free of VMS, and no recent MHT	CEE (0.3 mg; n = 6) CEE (0.625 mg; n = 6) ES (0.6 mg; n = 6) ES (1.2 mg; n = 6) E2 (1 mg; n = 6) Each woman took MHT daily for 25 days; six women took 2 different doses with drug-free interval of ≥1 month between doses	No significant changes in mean plasma lipid level except slight decreases in LDL-c from baseline by 0.625 mg CEE and 1 mg E2 (p < .05); No significant increase in HDL-c in any groups
Notelovitz et al. [24]	Prospective randomized study (15 months)	35 surgically menopausal women with bilateral oophorectomy and hysterectomy ≥3 months before baseline	Each woman was assigned a randomized sequence of a placebo, E2 (1 mg), E2 (2 mg), CEE (0.625 mg), and CEE (1.25 mg) Each regimen administered 3 of every 4 weeks for a 3-month period	Y: women <40 years; O: women ≥40 years Thrombin time (sec, mean ± SD): Placebo 17.5 ± 1.2 (Y); 17.3 ± 0.9 (O) 1 mg E2 15.3 ± 1.1 (Y); 15.7 ± 0.9 (O) 2 mg E2 18.4 ± 1.0 (Y); 16.7 ± 0.8 (O) 0.625 mg CEE 16.5 ± 0.9 (Y); 18.0 ± 1.1 (O) 1.25 mg CEE 16.0 ± 1.2 (Y); 17.9 ± 1.0 (O) p < .05 for 1 mg E2 vs placebo; p = NS for others Fibrinogen activity (mg/dL, mean ± SD): Placebo 387 ± 20 (Y); 375 ± 13 (O) 1 mg E2 413 ± 20 (Y); 403 ± 17 (O) 2 mg E2 362 ± 16 (Y); 386 ± 16 (O) 0.625 mg CEE 390 ± 15 (Y); 371 ± 18 (O) 1.25 mg CEE 393 ± 21 (Y); 367 ± 15 (O) p < .05 for 1 mg E2 vs placebo; p = NS for others α1-antitrypsin antigen (mg/dL, mean ± SD): Placebo 242 ± 7 (Y); 250 ± 19 (O) 1 mg E2 265 ± 10 (Y); 249 ± 12 (O) 2 mg E2 259 ± 14 (Y); 248 ± 11 (O) 0.625 mg CEE 259 ± 10 (Y); 251 ± 19 (O) 1.25 mg CEE 280 ± 13 (Y); 277 ± 15 (O) p < .02 for 1.25 mg CEE vs placebo; p = NS for others Plasminogen activity (cyano-trimethyl-androsterone U/mL, mean ± SD): Placebo 3.5 ± 0.2 (Y); 3.7 ± 0.2 (O) 1 mg E2 3.5 ± 0.2 (Y); 3.6 ± 0.2 (O) 2 mg E2 3.5 ± 0.1 (Y); 4.0 ± 0.1 (O) 0.625 mg CEE 3.8 ± 0.2 (Y); 4.0 ± 0.2 (O) 1.25 mg CEE 3.8 ± 0.2 (Y); 4.0 ± 0.1 (O) p < .002 for both CEE regimens vs placebo; p = NS for others
Man et al. [11]	Prospective cohort study (unspecified)	145 postmenopausal and premenopausal women aged 30–62 years	MHT user E2 only (2 mg/day; n = 29) CEE only (0.625 mg/day; n = 23) E2 + NETA (2 mg/1 mg; n = 23) Non-user Control A (≤5-year menopause; n = 22) Control B (>5-year menopause; n = 27) Control C (premenopausal; n = 21)	E2 or CEE only users vs nonusers: Significantly lower plasma levels of TC, LDL-c, ApoB, and TC/HDL-c ratio; Significantly higher HDL-c; No significant difference in triglycerides Similar changes with CEE and E2 in TC, LDL-c, HDL-c, triglycerides, ApoAI, and ApoB levels; Plasma homocysteine levels decreased 15% with E2, 13% with CEE, and 15% with E2/NETA.
Sweetland et al. [12]	Population-based prospective cohort study (MWS) (1996–2001)	1,058,259 postmenopausal women aged 50–64 years	In 86,250 current oral estrogen-only users: E2 (n = 19,818) CEE (n = 60,438) Never users (n = 476,711)	RR (95% CI) for VTE (current vs never use) E2: 1.45 (1.06–1.98) CEE: 1.46 (1.23–1.75) p = NS between groups
Smith et al. [27]	Retrospective case-control study (2003–2009)	384 postmenopausal women aged 30–79 years using oral MHT (183 cases of women who experienced an incident MI, ischemic stroke, or VTE, and 201 controls of women without a history of VTE, MI, or ischemic stroke)	Controls E2 (n = 114) CEE (n = 87) VTE cases E2 (n = 29) CEE (n = 39) MI cases E2 (n = 29) CEE (n = 38) Stroke cases E2 (n = 23) CEE (n = 25)	CEE vs E2 (current use) OR (95% CI) for VTE: 2.08 (1.02–4.27) MI: 1.87 (0.91–3.84) Ischemic stroke: 1.13 (0.55–2.31)
Blondon et al. [13]	Cross-sectional study (2003–2010)	282 postmenopausal women randomly selected from the controls of the HVH case-control study	Oral E2 (n = 93) Oral CEE (n = 48) Nonuser of MHT (n = 141)	CEE vs E2 (difference [95% CI]; P-value) TG peak (nM): +49.8 (21.0–78.6); 0.001 ETP (nMxMin): +175.0 (54.4–295.7); 0.005 TG lag-time (min): −0.01 (–0.26–0.25); 0.97 TG time to peak (min): −0.2 (–0.5–0.2); 0.27 Factor VII (%): −8.7 (–23.0–5.6); 0.23 Antithrombin (%): −2.7 (–8.4–3.0); 0.35 total protein S (%): −13.4 (–19.8– −6.9); p < .001 Differences compared with non-users in TG peak value, ETP, TG lag time, time-to-peak measures, and total protein S concentrations were more pronounced for CEE vs E2 users
Shufelt et al. [14]	Prospective cohort study (WHI-OS) (1994–2009)	41,721 postmenopausal women aged 50–79 years currently using MHT	MHT containing Oral E2 (n = 3024) Oral CEE (0.625 mg; n = 24,399)	E2 vs CEE HR (95% CI) for: Major CHD: 1.13 (0.79–1.61) Stroke: 0.64 (0.40–1.02) Total CVD: 0.93 (0.71–1.23)
Tsai et al. [29]	Population-based retrospective cohort study (1998–2008)	5489 menopausal women aged >45 years	E2 (n = 1815) CEE (n = 3674)	CEE vs E2 HR (95% CI) for AF: 1.96 (1.03–3.73) Stroke: 1.30 (1.04–1.62) MACE: 1.26 (1.03–1.54)
Vinogradova et al. [31]	Nested case-control study (1998–2017)	80,396 women aged 40–79 years with VTE, matched by 391,494 women as controls	Case/control Unopposed oral E2 (771/2781) Unopposed oral CEE (1208/4000) Opposed oral E2 (1582/5880) Opposed oral CEE (1354/4277)	OR (95% CI) for VTE (use vs nonuse) Unopposed oral E2: 1.27 (1.16–1.39) Unopposed oral CEE: 1.49 (1.39–1.60) Opposed oral E2: 1.59 (1.49–1.69) Opposed oral CEE: 1.91 (1.79–2.05) E2 vs CEE OR (95% CI) Unopposed: 0.85 (0.76–0.95), p = .005 Opposed: 0.83 (0.76–0.91), p < .001
Blondon et al. [32]	Retrospective cohort sudy (2003–2011)	51,571 peri- and postmenopausal women who were using MHT at the time of study entry or initiated MHT during the study period and were aged 40–64 years at the time of first MHT use	MHT containing Oral E2 (n = 6501; 16.8% with concomitant progestogens) Oral CEE (n = 38,421; 28.5% with concomitant progestogens)	Adjusted HR (95% CI) for incident VTE Oral E2 vs CEE (opposed and unopposed) All users: 0.96 (0.64–1.46) Incident users: 0.83 (0.42–1.62) Unopposed oral E2 vs CEE All users: 1.06 (0.69–1.63) Opposed oral E2 vs CEE All users: 0.30 (0.04–2.22)
P4 vs progestin
Writing group for the PEPI trial [66]	Prospective randomized controlled study (PEPI) (3 years)	875 postmenopausal women aged 45–64 years	CEE (0.625 mg) plus Cyclic MPA (10 mg; n = 174) Continuous MPA (2.5 mg; n = 174) Cyclic P4 (200 mg; n = 178) CEE alone (0.625 mg; n = 175) Placebo (n = 174) Cyclic progestogens taken on days 1 to 12 of a 28-day cycle	Significantly greater increase in HDL-c with CEE/P4 vs both CEE/MPA regimens; Similar decrease in LDL-c and increase in triglyceride with all MHT; TC significantly decreased with CEE/MPA regimens, but not CEE/P4, relative to placebo; No significant difference in effects on SBP or DBP with any MHT vs placebo (p = NS among groups)
Pélissier et al. [53]	Randomized parallel-group study (18 months)	336 postmenopausal amenorrheic women aged ≤57 years with intact uterus	TD E2 (1.5 mg) plus cyclic P4 (200 mg; n = 169) CMA (10 mg; n = 167) E2 taken on days 1 to 24 every month, combined with progestogens on days 11 to 24 of the month	P4 vs CMA at month 18: Change from baseline in plasma TC and triglycerides were small and similar between the two regimens; SBP and DBP decreased from baseline with E2/P4 and increased with E2/CMA (p < .05 between the two regimens)
Matthews et al. [77]	Randomized controlled study (8 weeks)	89 women aged 48–65 years	Estrogen^a (1.25 mg) plus continuous placebo (n = 18) MPA (5 mg; n = 18) P4 (100 mg; n = 17) Estrogen^a plus continuous methyl testosterone (n = 20) Placebo only (n = 16)	After 8-week MHT treatment: SBP reactivity during stress decreased significantly with estrogen/testosterone (p = .007), tended to decrease with estrogen/P4 (p = .095), but did not change with estrogen/MPA; DBP reactivity during stress increased with estrogen/MPA (p = .002), tended to decrease with estrogen/P4 (p = .06), but did not change with testosterone.
Canonico et al. [38]	Case–control study (ESTHER) (1996–2006)	271 consecutive cases with a first-documented idiopathic VTE and 610 controls matched for center, age, and admission date	MHT containing (case/control) P4 (19/63) Pregnane derivatives^b (39/79) Norpregnane derivatives^c (40/37)	ORs (95% CI) for VTE (current vs nonuse): P4: 0.7 (0.3–1.9) Pregnane derivatives: 0.9 (0.4–2.3) Norpregnane derivatives: 3.9 (1.5–10.0)
Canonico et al. [37]	Cross-sectional study (2006–2007)	108 postmenopausal women aged 45–70 years	TD E2 (50 μg) plus P4 (n = 30) Norpregnanes^c (n = 38) Nonuser (n = 40) P4 taken continuously at 100 mg/day or 12 days a month at 200 mg/day; norpregnanes (NOMAC or promegestone) taken continuously at 2.5 mg and 250 μg per day, respectively, or 12 days a month at a mean daily dose of 5 mg and 500 μg, respectively	Thrombin generation parameters: Significant higher APC resistance, peak height+APC, and ETP+APC with norpregnanes, vs no MHT use or P4; No significant difference with P4 versus no MHT use Hemostatic parameters: Significantly higher concentration of fragment 1 + 2 with norpregnanes vs no MHT; No significant difference with P4 versus no MHT use
Canonico et al. [36]	Prospective cohort study (E3N) (1990–2005)	80,308 postmenopausal women without personal history of thrombotic events before the start of follow up (549 first-documented incident VTEs [134 PE and 415 DVT]); taking MHT of various formulations and routes of administration	Never use (181 cases, 291,399 PY) MHT containing P4 (47 cases, 87,959 PY) Pregnane derivatives^b (91 cases, 125,804 PY) Norpregnane derivatives^c (69 cases, 78,855 PY) NETA (22 cases, 22,911 PY)	HRs (95% CI) for VTE (current vs never use): P4: 0.9 (0.6–1.5) Pregnane derivatives: 1.3 (0.9–2.0) Norpregnane derivatives: 1.8 (1.2–2.7) NETA: 1.4 (0.7–2.4)
Olié et al. [78]	Retrospective cohort study (MEVE) (2000–2008)	1023 postmenopausal women aged 45–70 years (893 non-MHT users; 130 MHT users) with a first confirmed VTE	Nonuser (68 cases, 6064 PY) TD estrogen plus P4 (3 cases, 231 PY) Pregnane derivatives^b (0 cases, 94 PY) Norpregnane derivatives^c (2 cases, 34 PY)	HRs (95% CI) for recurrent venous event (current vs nonuse) P4: 1.0 (0.3–3.2) Pregnane derivatives: NA Norpregnane derivatives: 4.7 (1.1–20.0) (Pheterogeneity = .22 between groups)
Scarabin et al. [39]	Cross-sectional study (unspecified)	115 healthy postmenopausal women, aged 25–65 years	Nonuser (n = 38) Oral estrogen plus P4 (n = 5) Progestins (n = 32) TD estrogen plus P4 (n = 17) Progestins (n = 19)	TD estrogen plus progestins vs P4: Higher ETP (p < .10) and peak (p≤.01) levels; Higher prothrombin levels (p < .05); Other thrombin generation parameters were similar between the two groups
Canonico et al. [35]	Nested case-control study (2009–2011)	Women aged 51–62 years without personal history of cardiovascular disease or gynecological cancers (3144 hospitalized ischemic stroke cases and 12,158 controls)	Nonuser (2950 cases, 11,331 controls) Current users of E2 plus P4 (60 cases, 380 controls) Pregnane derivatives (58 cases, 197 controls) Nortestosterone derivatives (17 cases, 46 controls) Norpregnane derivatives (17 cases, 27 controls)	Adjusted ORs (95% CI) for ischemic stroke (current vs nonuse): P4: 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)
Xue et al. [64]	Prospective open‑label randomized controlled study (1 year)	123 postmenopausal women with climacteric symptoms	CEE plus cyclic P4 0.3 mg/100 mg (n = 41) 0.625 mg/100 mg (n = 41) CEE plus cyclic DYD: 0.625 mg/10 mg (n = 41) Cyclic progestogens taken on days 17 to 28 of a 28-day cycle	Compared with baseline: Significant increase in triglycerides with CEE/DYD (p = .026); Significant increase in HDL-c and decrease in LDL-c with CEE/P4 (0.625 mg/100 mg; p = .033 and p = .039) and CEE/DYD (p = .006 and p = .029); No significant changes in SBP with any MHT; Significant decrease in DBP with CEE/P4 (0.3 mg/100 mg; p = .007), but not the other two regimens (p = NS)
Gao et al. [63]	Prospective randomized controlled study (24 months)	96 early postmenopausal women aged 40–60 years with climacteric symptoms	Oral E2V (1 mg) plus cyclic MPA (4 mg, n = 32) P4 (100 mg, n = 32) Cyclic progestogens taken on days 19 to 30 of a 30-day cycle	Compared with baseline at month 24: HDL-c significantly decreased with E2V/MPA (p = .019), but remained similar with E2V/P4; Triglycerides did not change significantly with either regimen; SBP and DBP did not change significantly with either regimen
Panay et al. [80]	Retrospective cohort study (2019–2021)	32,536 women aged ≥40 years who were initiated on E2/P4 (1 mg/100 mg) or CEE/MPA and did not have a VTE diagnosis in the 6 months pre-index	E2/P4 (1 mg/100 mg; n = 5288) CEE/MPA (n = 27,248)	HR (95% CI) for VTE (from the IPTW analyses of time to first VTE) E2/P4 vs CEE/MPA 0.59 (0.38–0.90), p < .05

AF: atrial fibrillation; APC: activated protein; ApoAI: apolipoprotein AI; ApoB: apolipoprotein B; CEE: conjugated equine estrogens; CHD: coronary heart disease; CI: confidence interval; CMA: chlormadinone acetate; CVD: cardiovascular disease; DBP: diastolic blood pressure; DYD: dydrogesterone; DVT: deep vein thrombosis; E2: estradiol; E2V: estradiol valerate; E3N: the Etude Epidémiologique de femmes de l’Education Nationale Study; ES: piperazine estrone sulfate; ESTHER: the Estrogen and Thrombo-embolism Risk study; ETP: endogenous thrombin potential; HDL-c: high-density lipoprotein cholesterol; HR: hazard ratio; HVH: Heart and Vascular Health Study; IPTW: inverse probability of treatment weighting; IRR: incidence rate ratio; LDL-c: low-density lipoprotein cholesterol; MACE: major adverse cardiac event; MEVE: the Menopause, Estrogen and Veins study; MHT: menopausal hormone therapy; MI: myocardial infarction; MPA: medroxyprogesterone acetate; NA: not applicable; NETA: norethisterone acetate; NOMAC: nomegestrol acetate; NS: not significant; OR: odds ratio; P4: progesterone; PE: pulmonary embolism; PEPI: the Postmenopausal Estrogen/Progestin Interventions study; PY: person-year; RR: relative risk; SBP: systolic blood pressure; TC: total cholesterol; TD: transdermal; TG: thrombin generation; VMS: vasomotor symptoms; VTE: venous thromboembolism; WHI-OS: the Women’s Health Initiate Observational Study; MWS: the Million Women Study.

Early postmenopausal: amenorrhea >6 months and <5 years.

^aContains primarily conjugated estrone.

^bPregnane derivatives included DYD, medrogestone, CMA, cyproterone acetate, and MPA.

^cNorpregnane derivatives included NOMAC and promegestone.

Figure 2. Outcomes with E2 versus CEE and P4 versus synthetic progestogens. (A) Cardiovascular outcome and breast cancer risks with estrogens. (B) Cardiovascular outcome risk with progestogens. (C) Breast cancer risk with progestogens.

AF: atrial fibrillation; CEE: conjugated equine estrogens; CHD: coronary heart disease; CI: confidence interval; CMA: chlormadinone acetate; CPA: cyproterone acetate; CVD: cardiovascular disease; der: derivatives; DYD: dydrogesterone; E: estrogen; E2: estradiol; Es: estrogens; HR: hazard radio; LNG: levonorgestrel; MACE: major adverse cardiac event; MDG: medogestone; MPA: medroxyprogesterone acetate; NETA: norethisterone acetate; NOMAC: nomegestrol acetate; OR: odds ratio; P: progestin; P4: progesterone; PMG: promegestone; RR: relative risk; TD: transdermal; VTE: venous thromboembolism.

Table 3. Studies comparing breast outcomes with E2 versus CEE and P4 versus synthetic progestogens.

Reference	Study design (duration)	Population	Treatment (dose; number of subjects)	Reported outcomes
E2 vs CEE
Bergkvist et al. [33]	Prospective cohort study (1977–1980)	23,244 women aged ≥35 years who filled ≥1 estrogen replacement prescription for menopause-related conditions	Estradiol compound (not defined) CEE Other estrogens (mainly estriols) (n for each group unspecified; some women took progestins concurrently)	RR (95% CI) for breast cancer (use vs nonuse): Estradiol compound: 1.2 (1.0–1.4) CEE: 1.1 (0.9–1.5) Other estrogens: 1.0 (0.8–1.3) RR increased with duration of treatment for estradiol compounds (Ptrend = .001) but not CEE (Ptrend = .7) and other estrogens (Ptrend = .7)
Cengiz et al. [30]	Retrospective study (1999–2001)	123 postmenopausal women with normal initial tumor marker levels and no previous use of MHT	Estrogen alone E2 (2 mg; n = 31) CEE (0.625 mg; n = 21) Continuous combined MHT E2/NETA (2 mg/1 mg; n = 37) CEE/MPA (0.625 mg/2.5 mg; n = 34)	Estrogen alone therapy: No effect was observed on serum CA125 II, CA19-9, CEA, and α-FP levels; CA15-3 level significantly decreased with E2 (p < .001), but not with CEE
Bülbül et al. [18]	Prospective cohort study (unspecified)	182 women with VMS, amenorrhea, and FSH >40 mIU/mL	Estrogen alone CEE (0.625 mg; n = 12) E2H (2 mg; n = 34) E2 (3.9 mg; n = 34) Sequential combined MHT CEE/MPA (0.625 mg/5 mg; n = 19) E2/NETA (2 mg/1 mg; n = 15) E2/MAP (2 mg/10 mg; n = 6) Continuous combined MHT CEE/MPA (0.625 mg/2.5 mg; n = 34) E2H/NETA (2 mg/1 mg; n = 8) Tibolone (2.5 mg; n = 18)	Incidence of increased mammographic density was higher with E2 (n = 12, 15%) versus CEE (n = 3, 3.8%)^a, p = NS.
Bakken et al. [15]	Prospective cohort study (EPIC) (1992–2000)	133,744 postmenopausal women without cancer at any site (30.9% women were current MHT users, of which 21.7% used estrogen-only MHT and 65.0% used combined estrogen/progestin MHT)	Current estrogen-only users CEE (21.4%) E2 (61.8%) Low-potency estrogens (11.3%) Other/unknown (5.5%) (MHT included oral and TD preparations)	RR (95% CI) for breast cancer (estrogen-only): Current vs never use: 1.42 (1.23–1.64) CEE vs E2 (current use): 1.15 (0.78–1.69)
Brusselaers et al. [16]	Prospective cohort study (2005–2012)	1,160,351 women aged ≥40 years without a history of malignancy (290,186 ever users with ≥1 MHT prescription and 870,165 never users with no MHT prescription and matched year of birth)	Estrogen only (n = 135,988) E2 (n = 53,339) Estriol (n = 55,653) Tibolone (n = 17,992) CEE (n = 1161) Estrogen/Progestogen (n = 154,198) Never user (n = 870,165) (84.0% of patients used oral MHT)	OR (95% CI) for breast cancer: Ever vs never use E2: 0.89 (0.84–0.94) CEE: 1.33 (1.00–1.77) Current vs never use E2: 1.12 (1.04–1.20) CEE: 4.47 (2.67–7.48)
Shufelt et al. [17]	Prospective cohort study (WHI-OS) (1993–2005)	26,525 postmenopausal women aged 50–79 years with a hysterectomy	Oral estrogen therapy E2 (n = 1226) CEE (<0.625 mg; n = 846) CEE (0.625 mg; n = 9903) CEE (>0.625 mg; n = 2004)	E2 vs CEE (0.625 mg) HR (95% CI) for breast cancer: Total 1.20 (0.84–1.39) <10 yr since menopause 1.46 (0.78–2.73) ≥10 yr since menopause 1.05 (0.67–1.66)
Zeng et al. [28]	Retrospective case-control study (unspecified)	40,046 women aged >50 years (12,404 cases of women who took any MHT after age 50 and 27,642 controls of women who did not take any MHT after age 50)	MHT cases CEE alone (n = 2556) MPA alone (n = 442) Other synthetic estrogen alone (n = 1349) Other synthetic progesterone alone (n = 417) Bioidentical estrogens^b alone (n = 1441) Bioidentical P4^c alone (n = 265) CEE/MPA (n = 453) Other synthetic estrogen/ synthetic P4 (n = 2512) Bioidentical estrogens/P4^b,^c(n = 288) Controls (n = 27,642)	HR (95% CI) for breast cancer: Ever vs never use CEE: 0.31 (0.25–0.38) Bioidentical estrogens: 0.65 (0.49–0.85)
Abenhaim et al. [34]	Nested case-control study (1995–2014)	43,183 women aged 50–75 years who had their first diagnosis of invasive breast cancer post-index, matched by 431,830 control women	Estrogen subgroups (cases/controls) No estrogen (36,391/373,019) Bioidentical estrogens^d (2487/21,579) CEE (3311/28184)	Breast cancer adjusted OR (95% CI) for ever use of any HT vs never use of estrogen: Bioidentical estrogens: 1.04 (1.00–1.09) CEE: 1.01 (0.96–1.06)
P4 vs progestin
Greendale et al. [68]	Randomized controlled study (PEPI) (3 years)	875 postmenopausal women aged 45–64 yearsv	CEE (0.625 mg) plus Cyclic MPA (10 mg; n = 174) Continuous MPA (2.5 mg; n = 174) Cyclic P4 (200 mg; n = 178) CEE alone (0.625 mg; n = 175) Placebo (n = 174) Cyclic progestogens taken days 1 to 12 of each 28-day cycle	Adjusted OR (95% CI) for breast discomfort: MHT vs placebo MPA (cyclic): 2.27 (1.39–3.56) MPA (continuous): 1.92 (1.16–3.09) P4: 2.33 (1.46–3.74) Between MHT regimens MPA (cyclic) vs P4: 0.97 (0.63–1.46) MPA (continuous) vs P4: 0.83 (0.53–1.26)
Greendale et al. [69]	Randomized controlled study (PEPI) (3 years)	307 women from PEPI who had not taken estrogen for ≥5 years before baseline and had baseline and follow-up mammograms	CEE (0.625 mg) plus Cyclic MPA (10 mg; n = 51) Continuous MPA (2.5 mg; n = 67) Cyclic P4 (200 mg; n = 55) CEE alone (0.625 mg; n = 58) Placebo (n = 64) Cyclic progestogens taken days 1 to 12 of each 28-day cycle	Incidence (95% CI) of BI-RADS grade increased at month 12: Cyclic MPA: 23.5% (11.9%–35.1%) Continuous MPA: 19.4% (9.9%–28.9%) Cyclic P4: 16.4% (6.6%–26.2%) p = NS between treatment groups Adjusted OR (95% CI) P4 vs cyclic MPA: 0.5 (0.2–1.8) P4 vs continuous MPA: 0.8 (0.8–2.5)
Cummings and Brizendine [55]	Prospective, randomized study (8 weeks)	23 early postmenopausal women aged <59 years with amenorrhea for >1 year	2 cycles of 2-week CEE (0.625 mg) followed by 2-week CEE (0.625 mg) plus P4 (200 mg; n = 13) or MPA (5 mg; n = 10)	P4 vs MPA: 31% (4/13) vs 70% (7/10) Fewer self-reported breast tenderness cases, no statistical analysis performed
Greendale et al. [70]	Randomized controlled study (PEPI) (3 years)	571 women from PEPI with baseline and follow-up mammograms	CEE (0.625 mg) plus Cyclic MPA (10 mg; n = 109) Continuous MPA (2.5 mg; n = 121) Cyclic P4 (200 mg; n = 115) CEE alone (0.625 mg; n = 114) Placebo (n = 112) Cyclic progestogens taken days 1 to 12 of each 28-day cycle	Incidence (95% CI) of mammographic density increased at month 12: Placebo: −0.1% (–1.5%–1.4%) Cyclic MPA: 4.8% (3.3%–6.2%) Continuous MPA: 4.6% (3.2%–6.0%) Cyclic P: 3.1% (1.7%–4.5%) p = NS between MHT groups
Fournier et al. [45]	Prospective cohort study (E3N-EPIC) (1990–2000)	29,420 postmenopausal women taking MHT (mostly E2 based, only 1.9% of CEE use) and 25,128 not using MHT	Breast cancer (case/PY) with estrogens/oral progestogens: TD Estrogen/P4 (55/20,685) TD Estrogen/progestins (187/46,242) Oral Estrogen/progestins (80/20,504)	Adjusted RR (95% CI) of breast cancer (incident vs never use) TD estrogen/P4: 0.9 (0.7–1.2) TD estrogen/progestins: 1.4 (1.2–1.7) Oral estrogen/progestins: 1.5 (1.1–1.9) <2 years MHT duration TD estrogen/P4: 0.9 (0.6–1.4) TD estrogen/progestins: 1.6 (1.3–2.0) Oral estrogen/progestins: 1.2 (0.9–1.8) 2–4 years MHT duration TD estrogen/P4: 0.7 (0.4–1.2) TD estrogen/progestins: 1.4 (1.0–1.8) Oral estrogen/progestins: 1.6 (1.1–2.3) ≥4 years MHT duration TD estrogen/P4: 1.2 (0.7–2.0) TD estrogen/progestins: 1.2 (0.8–1.7) Oral estrogen/progestins: 1.9 (1.2–3.2)
Crandall et al. [71]	Prospective, randomized controlled study (PEPI-MDS) (12 months)	533 postmenopausal women (45–64 years) from PEPI without major contraindication to estrogen/progestin therapy (e.g. breast cancer) or breast discomfort at baseline	Breast density CEE (0.625 mg) plus Cyclic MPA (10 mg; n = 99) Continuous MPA (2.5 mg; n = 112) Cyclic P4 (200 mg; n = 105) CEE alone (0.625 mg; n = 105) Placebo (n = 103) Breast discomfort CEE (0.625 mg) plus Cyclic MPA (10 mg; n = 100) Continuous MPA (2.5 mg; n = 112) Cyclic P4 (200 mg; n = 109) CEE alone (0.625 mg; n = 108) Placebo (n = 104) Cyclic progestogens taken on days 1 to 12 of each 28-day cycle	Incidence of mammographic density increased at month 12 Placebo: −0.4% CEE/cyclical MPA: 4.6% CEE/continuous MPA: 4.4% CEE/cyclical P4: 3.1% Incidence of new-onset breast discomfort at month 12 Placebo: 12.5% CEE/cyclical MPA: 28.0% CEE/continuous MPA: 23.2% CEE/cyclical P4: 27.5% Significantly different from placebo; p = NS between MHT groups
Espié [50]	Prospective phase of the MISSION study (2004–2006)	4949 postmenopausal women without breast cancer, exposed or unexposed to MHT	Unexposed (n = 2256) Exposed (n = 2693) E2 alone E2 plus progestogen E2/P4 (43.7%) E2/Progestins (56.3%; excluding MPA and 19-nortestosterone derivatives) (Route of progestogens unspecified)	Breast cancer incidence: E2/P4: 0.40% E2/progestins: 0.94% p = NS between treatment groups RR (95% CI) for breast cancer (use vs no use): TD E2/P4: 0.46 (0.13–1.62) TD E2/progestins: 1.07 (0.5–2.27) Oral E2/progestins: 0.81 (0.23–2.85)
Fournier et al. [46]	Prospective cohort study (E3N) (1990–2002)	80,377 postmenopausal women without a history of cancer other than a basal cell carcinoma at baseline (23,703 never users and 56,674 ever users of MHT)	Oral estrogens (cases/PY): P4 (<5 cases) MPA (29/7035) NETA (46/7401) DYD (7/3217) Medrogestone (9/1104) CMA (8/1431) CPA (34/4779) Promegestone (13/2814) NOMAC (8/2623) TD estrogens (cases/PY): P4 (121/35,513) MPA (<5 cases) NETA (<5 cases) DYD (90/25,405) Medrogestone (28/4590) CMA (35/7774) CPA (<5 cases) Promegestone (69/14,910) NOMAC (91/18,826)	RR (95%) for invasive breast cancer (ever vs never use) Oral estrogens plus P4: number of cases too low to analyze MPA: 1.48 (1.02–2.16) NETA: 2.11 (1.56–2.86) DYD: 0.77 (0.36–1.62) Medrogestone: 2.74 (1.42–5.29) CMA: 2.02 (1.00–4.06) CPA: 2.57 (1.81–3.65) Promegestone: 1.62 (0.94–2.82) NOMAC: 1.10 (0.55–2.21) TD estrogens plus P4: 1.08 (0.89–1.31) DYD: 1.18 (0.95, 1.48) Medrogestone: 2.03 (1.39–2.97) CMA: 1.48 (1.05–2.09) Promegestone: 1.52 (1.19–1.96) NOMAC: 1.60 (1.28–2.01) MPA, NETA, CPA: number of cases too low to analyze <2 yrs MHT duration P4: 0.71 (0.44–1.14) DYD: 0.84 (0.51–1.38) Other progestogens: 1.36 (1.07–1.72) 2–4 yrs MHT duration P4: 0.95 (0.67–1.36) DYD: 1.16 (0.79–1.71) Other progestogens: 1.59 (1.30–1.94) 4–6 yrs MHT duration P4: 1.26 (0.87–1.82) DYD: 1.28 (0.83–1.99) Other progestogens: 1.79 (1.44–2.23) ≥6 yrs MHT duration P4: 1.22 (0.89–1.67) DYD: 1.32 (0.93–1.86) Other progestogens: 1.95 (1.62–2.35)
Fournier et al. [47]	Prospective cohort study (E3N) (1990–2002)	80,391 postmenopausal women without a history of cancer except cell carcinoma (23,725 never users and 56,666 ever users of MHT)	Ductal cases Estrogen/P4 (n = 87) Estrogen/DYD (n = 70) Estrogen/other progestogens (n = 334) Lobular cases Estrogen/P4 (n = 24) Estrogen/DYD (n = 28) Estrogen/other progestogens (n = 113)	RR (95%) (ever vs never use) Ductal breast cancer P4: 1.0 (0.8–1.3) DYD: 1.1 (0.9–1.4) Other progestogens: 1.6 (1.3–1.8) Lobular breast cancer P4: 1.1 (0.7–1.7) DYD: 1.7 (1.1–2.6) Other progestogens: 2.0 (1.5–2.7)
Fournier et al. [48]	Prospective, cohort study (E3N) (1990–2005)	53,310 postmenopausal women without a history of cancer except basal cell carcinoma (21,231 never users and 32,079 ever users of MHT)	Invasive breast cancer cases Estrogen/P4 (n = 210) Estrogen/DYD (n = 150) Estrogen/other progestogen (n = 577)	HR (95% CI) invasive breast cancer (recent vs never use) MHT initiated ≤3 years from menopause ≤2 yrs MHT duration P4: 0.87 (0.57–1.32) DYD: 1.44 (0.99–2.09) Other progestogen: 1.89 (1.53–2.34) 2–5 yrs MHT duration P4: 1.01 (0.72–1.41) DYD: 1.21 (0.85–1.72) Other progestogen: 1.88 (1.56–2.27) 5–10 yrs MHT duration P4: 1.47 (1.11–1.95) DYD: 1.38 (0.98–1.93) Other progestogen: 1.87 (1.54–2.27) >10 yrs MHT duration P4: 1.92 (1.34–2.74) DYD: 1.35 (0.81–2.26) Other progestogen: 2.32 (1.76–3.06) MHT initiated >3 years from menopause ≤2 yrs MHT duration P4: 0.90 (0.45–1.81) DYD: 1.14 (0.51–2.55) Other progestogen: 1.02 (0.59–1.78) 2–5 yrs MHT duration P4: 1.55 (0.96–2.48) DYD: 0.95 (0.42–2.13) Other progestogen: 1.79 (1.22–2.63) 5–10 yrs MHT duration P4: 0.89 (0.50–1.59) DYD: 1.77 (1.02–3.09) Other progestogen: 2.21 (1.56–3.14) >10 yrs MHT duration P4: 0.97 (0.36–2.62) DYD: 1.83 (0.68–4.93) Other progestogen: 1.07 (0.40–2.87)
Cordina-Duverger et al. [79]	Population-based, case-control study (2005–2007)	1555 menopausal women aged 25–75 (739 incident cases of in situ or invasive breast cancer and 816 controls without prior history of breast cancer)	Breast cancer (case/control) Estrogen plus P4 (25/34) Progestins (67/48) P4 derivatives (55/43) Testosterone derivatives (11/5) Never use (311/357)	ORs (95% CI) for breast cancer (current vs nonuse) P4: 0.80 (0.44–1.43) Progestins: 1.72 (1.11–2.65) P4 derivatives: 1.57 (0.99–2.49) Testosterone derivatives: 3.35 (1.07–10.4) <4 yrs MHT duration P4: 0.69 (0.29–1.68) Progestins: 1.17 (0.48–2.86) P4 derivatives: 1.02 (0.40–2.58) Testosterone derivatives: 1.64 (0.38–7.15) (n < 5) ≥4 yrs MHT duration P4: 0.79 (0.37–1.71) Progestins: 2.07 (1.26–3.39) P4 derivatives: 1.92 (1.13–3.27) Testosterone derivatives: 9.47 (1.09–82.6) (n < 5)
Zheng et al. [57]	Prospective, randomized study (3 months)	96 early postmenopausal women aged 40–60 years with climacteric symptoms	Oral E2V plus oral, cyclic P4 (n = 32) MPA (n = 32) Cyclic progestogens taken on days 19 to 30 of a 30-day cycle	Breast tenderness incidence in 3 months P4: 36.7% MPA: 14.3%
Fournier et al. [49]	Prospective, cohort study (E3N) (1990–2008)	78,353 postmenopausal women without a history of cancer except basal cell carcinoma (31,223 never users, 21,601 past users, and 17,986 current users of MHT)	Invasive breast cancer cases Never use (n = 890) Current use of estrogen plus P4/DYD (n = 638) Other progestogens^e (n = 931) Past use of estrogen plus P4/DYD (n = 552) Other progestogens^e (n = 708)	HR (95% CI) for invasive breast cancer Current vs never use P4/DYD: 1.22 (1.11–1.35) Other progestogens 1.87 (1.71–2.04) Past vs never use P4/DYD: 0.96 (0.87–1.06) Other progestogens 1.12 (1.02–1.23)
Asi et al. [41]	Meta-analysis	3 comparative/controlled studies of women aged 45–59 years, <10 years from menopause, followed up for ≥6 months (2 studies compared progesterone with progestins)	Estrogens plus P4 Progestins	RR (95% CI) for breast cancer: P4 vs progestins 0.67 (0.55–0.81)
Yang et al. [42]	Meta-analysis	9 observational comparison studies with combined MHT containing opposed or unopposed E2 or E2V; peri/postmenopausal women who received MHT (including hysterectomized with ovaries)	E2/E2V plus MPA (2 studies) LNG (2 studies) NETA (4 studies) DYD (3 studies) P4 (2 studies) Mixed progestogens (6 studies) (route of progestogens unspecified)	Pooled ORs (95% CI) for breast cancer MPA: 1.19 (1.07–1.33) LNG: 1.47 (1.17–1.85) NETA: 1.44 (1.26–1.65) DYD: 1.10 (0.89–1.36) P4: 1.00 (0.83–1.20) Mixed progestogens: 1.99 (1.57–2.52)
Zeng et al. [28]	Retrospective case-control study (unspecified)	40,046 women aged >50 years (12,404 cases: women who took any MHT after age 50; 27,642 controls: women who did not take any MHT after age 50	MHT cases CEE/MPA (n = 453) Synthetic estrogen/ synthetic progestins (n = 2512) Bioidentical estrogens/P4^b,^c (n = 288)	HR (95% CI) for breast cancer (ever vs never use) CEE/MPA: 0.43 (0.28–0.67) Synthetic estrogens/synthetic progestins: 1.03 (0.84–1.27) Bioidentical estrogens/P4: 1.05 (0.59–1.85) CEE/MPA vs bioidentical estrogens/P4^b,^c: 0.25 (0.12–0.55)
Gao et al. [65]	Prospective, randomized, controlled study	96 early postmenopausal women aged 40–60 years	Oral E2V (1mg) plus cyclic MPA (4 mg; n = 32) P4 (100 mg; n = 32) Cyclic progestogens taken on days 19 to 30 of a 30-day cycle	Breast tenderness incidence in 12 months: MPA: 80.8% P4: 72.0% (p = NS between groups)
Wang et al. [58]	Prospective, randomized study	96 early postmenopausal women aged 40–60 years	Oral E2V (1 mg) plus cyclic P4 (4 mg; n = 32) MPA (100 mg; n = 32) Cyclic progestogens taken on days 19 to 30 of a 30-day cycle	Breast pain incidence in 6 months: MPA: 71.4% P4: 62.1% (p = NS between groups) No significant differences in duration of breast pain; Pain intensity was similar
Abenhaim et al. [34]	Nested case-control study (1995–2014)	43,183 women aged 50–75 years who had the first diagnosis of invasive breast cancer post-index, matched by 431,830 women as controls	Progestogen subgroups (cases/controls) No progestogen (40,352/410,256) P4 (12/125) Progestins^f (2817/21,434) Both progestogen formulations (2/15)	Breast cancer adjusted OR (95% CI) for ever use of any HT vs never use of progestogen: P4: 0.99 (0.55–1.79) Progestins: 1.28 (1.22–1.35)

BI-RADS: Breast Imaging Reporting and Data System; CEE: conjugated equine estrogens; CI: confidence interval; CMA: chlormadinone acetate; CPA: cyproterone acetate; DYD: dydrogesterone; E2: estradiol; E2H: estradiol hemihydrate; E2V: estradiol valerate; E3N: the Etude Epidémiologique de femmes de l’Education Nationale Study; EPIC: the European Prospective Investigation into Cancer and Nutrition study; FSH: follicle-stimulating hormone; HR: hazard ratio; LNG: levonorgestrel; MHT: menopausal hormone therapy; MISSION: the Menopause: Risk of Breast Cancer, Morbidity and Prevalence study; MPA: medroxyprogesterone acetate; NETA: norethisterone acetate; NOMAC: nomegestrol acetate; NS: not significant; OR: odds ratio; P4: progesterone; PEPI: the Postmenopausal Estrogen/Progestin Interventions study; PEPI-MDS: the PEPI Mammographic Density Study; RR: relative risk; TD: transdermal; VMS: vasomotor symptoms; WHI-OS: the Women’s Health Initiate Observational Study.

Early postmenopausal: amenorrhea >6 months and <5 years.

^aCalculation of percentages not consistent with n in each group, not clear in paper how it was calculated.

^bBioidentical estrogens included: estradiol oral, Estrace oral, 17β-estradiol, micronized estrogen, estradiol acetate oral, estradiol hemihydrate oral, Gynodiol oral, Femtrace, Innofem, estradiol acetate oral, Delestrogen, estradiol valerate, estradiol cypionate, Depo-Estradiol, estradiol transdermal, Alora, Climara, Esclim, Estraderm, Vivelle, Vivelle-Dot, Dot, Estrogel, Estrasorb, Estradiol Transdermal, Transdermal Estradiol, Fem-Patch, Menostar, Elestrin, Divigel, Evamist, Estrasorb, Minivelle (as reported).

^cBioidentical progesterone included: micronized progesterone, Prometrium, Prochieve, Crinone (as reported).

^dBioidentical estrogens included: estradiol (Estraderm, Evorel, Oestrogel, FemSeven, Elleste Solo, Sandrena, Progynova, Fematrix, Zumenon, Estradot, Menorest, Dermestril, Bedol, Nuvelle TS Phase 1, Adgyn, Indivina), estriol (Ovestin), estrone (piprazine estrone sulfate, Improvera), and a tri-estrogen formulation containing estriol, estradiol, and estrone (Hormonin).

^eOther progestogens included: CMA, CPA, demegestone, dienogest, drospirenone, ethynodiol acetate, gestodene, LNG, lynestrenol, medrogestone, MPA, nomegestrol acetate, NOMAC, NETA, and promegestone.

^fProgestins included: predominantly MPA (Depo-provera, Provera, Sayana Press, Climanor, Premique, Indivina), norgestrel, and levonorgestrel (FemSeven).

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