The impact of micronized progesterone on the endometrium: a systematic review

Figures & data

Table 1. Literature search strategy (PICO criteria); status March 2015.

E1	Population/Patient	All (post/perimenopausal) women (natural or surgical menopause) using systemic estrogen replacement therapy (estradiol or conjugated equine estrogen; estriol and estrogen were excluded)
E2	Intervention	Progesterone (natural), exogenously administered on oral, transdermal or vaginal route; duration of study at least 3 months; in humans
E3	Comparison/control	Synthetic progestogens, placebo, no comparison
E4	Outcome	Endometrium hyperplasia or endometrium carcinoma, endometrial biopsies investigating proliferative/antiproliferative effects, endometrial transformation or atrophy
E5	Article type	Clinical studies, observational/epidemiological studies (meta-analyses and systematic reviews were included in order to search for secondary literature)
E6	Language	All English and German abstracts

Table 2. Overview of trials investigating menopausal hormone therapy (MHT) containing oral micronized progestin (MP).

					Dosage and application regimen		Endometrium
Reference	Study design	Sample size^a	Study duration	Reproductive stage^c	Progestogen	Estrogen	Thickness^b	Histology (biopsy)	Results
Writing Groupfor PEPI^15	PC-RCT	596/527 (biopsies)	3 years	Post	Oral MPA 10 mg/day days 1–12, oral MPA 2.5 mg/day, oral MP 200 mg/day days 1–12	Oral CEE 0.625 mg/day	No	Yes: baseline and annually without regard to woman’s menstrual cycle	Histology in placebo group (n = 119): normal n = 116, simple hyperplasia n = 1, complex hyperplasia n = 1, adenocarcinoma n = 1; in CEE-only group (n = 119): normal n = 45, simple hyperplasia n = 33, complex hyperplasia n = 27, atypia n = 14; in CEE + MPA (sequential) group (n = 118): normal n = 112, simple hyperplasia n = 4, complex hyperplasia n = 2; in CEE + MPA (continuous) group (n = 120): normal n = 119, simple hyperplasia n = 1; in CEE + MP (sequential) (n = 120): normal n = 114, simple hyperplasia n = 5, atypia n = 1; significant difference for CEE vs. placebo, p < 0.001)
Harman^9	PC-RCT	727/464	37.4 ± 16.6 months	Post	Oral MP 200 mg/day on days 1–12 of each month	Oral CEE 0.45 mg/day or transdermal E2 50 μg/day	No	No	Endometrial cancer assessed as adverse events; no significant difference between MHT and placebo
Prestwood^21	PC-RCT	167/112	3 years	Post	Oral MP 100 mg/day for 2 weeks every 6 months	Oral E2 0.25 mg/day	Yes: baseline and every 6 months	Yes: after 3 years	Endometrial thickness: slight increase, but no significant difference between groups except at year 2; no significant difference in histology, one case of hyperplasia in each group
Jondet^18	RCT	336/244 (biopsies)	6-month double-blind, then 12-month open-label	Post	Group 1: oral CMA 10 mg/day; group 2: oral MP 200 mg/day on days 10–24	Transdermal E2 1.5 mg/day on days 1–24	No	Yes: baseline 18 months (days 10–24)	Histology at baseline: atrophic in 91.8%, proliferative in 4.1%, secretory in 3.3%; for E2 + CMA at month 18: atrophic in 19.5%, proliferative in 3.7%, secretory in 76.8%; for E2 + MP at month 18: atrophic in 27.1%, proliferative in 8.3%, secretory in 62.5%
Holst^17	RCT	32/6 for histomor-phometry	6 months	Post	Group 1: oral MP 200 mg/day on days 11–21; group 2: oral MP 300 mg/day on days 11–21	Transdermal E2 3 mg/day for 21 days per month	No	Yes: baseline, at 6 months before and at end of MP application	Histology and histomorphometry at baseline: all atrophic; at month 6: no significant changes in areas of glandular cells, glandular nuclei and stromal nuclei with any MP dosage
Moyer^24	RCT	107 (21 premenopausal controls)/64 (19)	4 25-day cycles (1 cycle CEE only, then RCT)	Post	Group 1: oral MP 100 mg/day; group 2: oral MP 200 mg/day; group 3: oral MP 300 mg/day; group 4: oral MP 400 mg/day for 10 days/25-day cycle	Oral CEE 0.625 mg/day for 25 days	No	Yes: baseline (after CEE only) to after 3 EPT cycles (day 26)	Proliferation index (MIB): significant reduction in MP 200–400 mg/day and luteal phase compared to CEE only; no difference for 100 mg/day; secretory maturation: 0 in CEE-only, 2/22 in MP 100 mg/day, 5/25 in MP 200 mg/day, 10/19 in MP 300 mg/day, 14/22 in MP 400 mg/day, all premenopausal women in luteal phase, 1 simple hyperplasia without atypia in MP 300 mg/day
Dupont^13	Single-blinded RCT	63; groups 1 and 2 (hysterectomy) n1 = 16, n2 = 15; groups 3 and 4 (intact uterus) n3 = 16, n4 = 16	24 weeks	Post	Groups 3 and 4: oral MP 200 mg/day on days 12–25 each month	Groups 1 and 3: transdermal E2 1.5 mg/day; groups 2 and 4: oral CEE 0.625 mg/day for 25 days each month (dosage adjusted during first 3 cycles according to symptoms)	No	Yes: baseline, week 24	Histology baseline–week 24: atrophic in 23/32–18/32, proliferative in 7/32–10/32, mixed in 1/32–3/32 (cave: one is missing)
Darj^12	RCT head-to-head comparison	30/26	4 months	Post	Oral MP group 1: 50 mg/day; group 2: 100 mg/day; group 3: 200 mg/day for 25 days each month	Oral E2 2 mg/day for 25 days each month	No	Yes: baseline, month 4	Histology at baseline and month 4 for group 1: atrophic in 80% and 60%, proliferative in 10% and 20%, secretory in 10% and 10% (dropout 10%); for group 2: atrophic in 90% and 60%, proliferative in 10% and 0%, secretory in 0% and 10% (3 dropouts; for group 3: atrophic in 70% and 100%, proliferative in 20% and 0%, secretory in 10% and 0%
Di Carlo^5	Open-label RCT	100/80	12 cycles	Post	Group A: oral MP 100 mg/day; group B: oral MP 200 mg/day; group C: vaginal MP 100 mg/day; group D: vaginal MP 200 mg/day; sequential regimen (14–25th cycle day/28-day cycle)	Transdermal E2patch 50 μg/day	Yes: baseline, end of trial (after progestogen withdrawal bleeding)	No	No significant group differences at baseline and after 12 cycles; significant increase of endometrial thickness when comparing endometrial thickness at baseline and after 12 cycles for groups A–C, but below 6 mm in all cases
Di Carlo^6	Open-label RCT	100/79	12 cycles	Post	Group A: oral MPA 10 mg/day; group B: oral NOMAC 5 mg/day; group C: oral DYD 10 mg/day; group D: oral MP 200 mg/day; sequential regimen (14–25th cycle day/28-day cycle)	Transdermal E2patch 50 μg/day	Yes: baseline, end of trial (after progestogen withdrawal bleeding)	No	No significant group differences at baseline and after 12 cycles; significant increase of endometrial thickness when comparing endometrial thickness at baseline and after 12 cycles for all groups, but below 6 mm in all cases
Pelissier^22	RCT	336/265	18 months (6 months double-blind, 12 months open-label)	Post	Group 1: oral CMA 10 mg/day; group 2: oral MP 200 mg/day from day 11to 24	Transdermal E2 1.5 mg/day from day 1 to 24/cycle	No	Yes: baseline,months 6 and 18	Baseline CMA: insufficient in 13.7%, atrophic in 75.6%, inactive in 4.4%, secretory in 3.8%, proliferative in 1.9%; baseline MP: insufficient in 16.6%, atrophic in 70.7%, inactive in 5.1%, secretory in 1.9%, proliferative in 5.1%; CMA at month 18: atrophic in 15.8%, inactive in 3.7%, secretory in 76.8%, proliferative in 3.7%, treatment success 63.7%, treatment failure 2.4%; MP at month 18: atrophic in 20.8%, inactive in 3.6%, secretory in 62.5%, proliferative in 8.3%, treatment success 35.8%, treatment failure 3.3%
Lane^19	Non-randomized prospective trial	50	12 months	Post	Group 1: oral MP 300 mg/day; group 2: oral MP 200 mg/day; group 3: oral MP 100 mg/day from day 1 to 10 of the calendar month	Oral CEE 1.25 mg/day	No	Yes: at month 3 on day 6	Histology in group 1 (n = 12): 83% with varying degrees of secretory change, 17% with non-secretory pattern; in group 2 (n = 13): 69% with early secretory changes mixed with proliferative or non-secretory type glands, 23% with non-secretory pattern; in group 3 (n = 11): 36% with varying degrees of secretory change, 27% with non-secretory pattern, 27% with mild to moderate atypical hyperplasia. Additional methods: transmission electron microscopy, biochemistry
Hargrove^16	Non-randomized prospective trial	17/15	12 months	Peri, n = 4; post, n = 13	Group 1: oral MP 2–3 × 100 mg/day; group 2: oral MPA 10 mg/day from day 1 to 10 of the calendar month	Group 1: oral E2 2–3 × 0.35 mg/day; group 2: oral CEE 0.625 mg/day	Yes: baseline, 1, 3, 6, 12 months	Yes: baseline, 1, 3,6, 12 months	Endometrial thickness (only data at study completion provided): CEE + MP <2 mm, CEE + MPA no pathology; Histology (only data at 6 months provided): CEE + MP atrophy, CEE + MPA proliferative or secretory
Foidart^26	Non-randomized prospective trial	50 post- and 30 premenopausal women/50 post- and 30 premenopausal women	3–6 months	Post and pre	Group 2: oral MP 100 mg/day across 25 days/month	Group 1: estrogen only (oral CEE 0.625 mg/day or transdermal E2 1.5 mg/day for 3 months), followed by 3 months of combined EPT regimen (oral MP 100 mg/day across 25 days/month); group 2: transdermal E2 1.5 mg/day across 25 days/month	No	Yes: baseline, 3rd EPT cycle (cycle days 21–25)	No distinct secretory pattern nor hyperplasia; preferably mild proliferative pattern; mitotic activity and DNA synthesis increased in ET but reduced in EPT group
Suvanto-Luukkonen^23	Non-randomized prospective trial	30/27	24 months	Post	Group 1: LNG-IUD (20 μg/day); group 2: oral MP 200 mg/day for 25 days per calendar month; group 3: vaginal MP 100–200 mg/day on 25 days per calendar month	Transdermal E2 1.5 mg/day	No	Yes: baseline, 12,24 months	Histomorphology at baseline: atrophic in 10/14, mild proliferation in 3/14, inactive in 1/14; for LNG at month 24: atrophic in 15/16, partly proliferative in 1/16; for oral MP at month 24: proliferative in 9/10, inactive in 1/10; for vaginal MP at month 24: inactive in 3/3
Gillet^14	Non-randomized prospective trial	101/91; high-dose n = 3, low-dose n = 98	6 months	Post	Group 1 (high dose): oral MP 300 mg/day from day 16 to 25; group 2 (low-dose): oral MP 100 mg/day from day 1 to 21or 25	Group 1 (high-dose): transdermal E2 3 mg/day from day 1 to 25 of each calendar month; group 2 (low-dose): transdermal E2 1.5 mg/day from day 1 to 21 per cycle or day 25 of the calendar month (dosage could be adapted during the first 3 months according to symptoms)	Yes, if biopsy was insufficient	Yes: after 6 months after at least 12 days of MP during that cycle	Mitoses count in glandular epithelial cells; group 1 (n = 2): no mitosis or 1 mitosis/1000 cells, group 2 (n = 78): insufficient in 3.8%, atrophic in 3.8%, quiescent in 61.5%, mildly active in 23.1%, partially secretory in 7.7%
Bolaji^10	Open prospective trial	40/32	12 months	Post	Oral MP 100 mg/day for 23 days of every calendar month	Oral CEE0.625 mg/day	Yes: baseline,end of trial	Yes: baseline, 6 months, 12 months between days 20 and 23	Endometrial thickness without change; Histology at baseline: atrophic in 74%, proliferative in 15%, secretory in 7%, simple hyperplasia in 2%; after 12 months: atrophic in 73%, proliferative in 17%, secretory in 7%, simple hyperplasia in 3%
Bolaji^11	Open prospective trial	40/29	12 months	Post	Oral MP 100 mg/day for 23 days of every calendar month	Oral CEE 0.625 mg/day	No	Yes: baseline, 6 months, 12 months between days 20 and 23	Histomorphology at baseline: inadequate in 7%, atrophic in 47%, secretory in 7%, proliferative in 15%, cystic hyperplasia in 2%; at month 12: atrophic in 17%, secretory in 7%, proliferative in 17%, cystic hyperplasia in 3%
Allen^7	Prospective cohort study	115 474	Mean follow-up 9.0 years	Post	Current MHT user 29%, combined estrogen–progestogen therapy 74% (sequential regimen 45%, continuous regimen 16%) containing synthetic progestins (91%) or MP (9%)	Estrogens not further specified	No	No	Endometrial cancer. HR (95% CI): current MHT use 1.41 (1.08–1.83), sequential MHT regimen 1.52 (1.00–2.29), continuous MHT regimen 0.24 (0.08–0.77), MP as progestogen constituent 2.42 (1.53–3.83)
Fournier^8	Prospective cohort study	65 630	Mean follow-up 10.8 years	Post	Percentage of current MHT users is not provided; 40.2% of combined estrogen–progestogen therapy contained oral MP for a mean duration of 4.2 years	E2 92.8%, CEE 2.2%, weak estrogens (estriol, promestriene) 11.1%	No	No	Endometrial cancer. HR (95% CI): any MHT use 1.33 (1.01–1.76), MP as progestogen constituent: ever use 1.80 (1.38–2.34), current use 1.96 (1.41–2.73), use for ≤5 years 1.39 (0.99–1.97) and for >5 years 2.66 (1.87–3.77)
Marengo^25	Prospective controlled trial	112/110	12 months	Post	Oral MP 100 mg/day for 25 days percalendar month	Transdermal E2 1.5 or 0.75 mg/day for 25 days per calendar month	Yes, but only if inadequate tissue (n = 5)	Yes: baseline, 2, 6,12 months	At 12 months: atrophy 81%, sub-atrophy 14.5%, inadequate tissue 4.5% (mean endometrial thickness in those 3 mm)
Moyer^20	Observational expanded clinical case report	236/153 (n = 53 with adequate tissue)	5 years	Post	Oral MP 200 mg/day 14 days/28 days (increase to 300 mg/day and/or shorten to 10–12 days if required)	Transdermal E2 1.5 mg/day on 21 days/28 days (increase to 3 mg and/or 25 days according to symptoms)	No	Yes: after 5 years at day 2–14 of MP treatment (hysteroscopy + biopsy if no tissue was obtained)	Histology: no hyperplasia or carcinoma, in none of the biopsies did the quantity of secretory maturation equal a fully developed glandular and stromal pattern equivalent to late luteal phase. Moderate secretory maturation in 78% of high E2/high MP group (3/300 for 10 days) but only in 8% of low E2/low MP group (1.5/200 for 14 days)

a , recruited/analyzed; ^b, measured by transvaginal ultrasound; ^c, post, postmenopause, pre, premenopause; peri, perimenopause

PEPI, Postmenopausal Estrogen/Progestin Interventions Trial; PC-RCT, placebo-controlled, randomized controlled trial; RCT, randomized controlled trial; CEE, conjugated equine estrogen; E2, 17β-estradiol; MPA, medroxyprogesterone acetate; CMA, chlormadinone acetate; NOMAC, nomegestrol acetate; DYD, dydrogesterone; LNG-IUD, levonorgestrel-releasing intrauterine device; EPT, estrogen–progestogen therapy; ET, estrogen therapy; HR, hazard ratio; 95% CI, 95% confidence interval

Table 3. Overview of trials investigating menopausal hormone therapy (MHT) containing vaginal micronized progestin (MP).

				Dosage and application regimen		Endometrium
Reference	Study design	Sample size^a	Study duration	Progestogen	Estrogen	Thickness^b	Histology (biopsy)	Results
Ben-Chetrit^28	RCT	29/18	4–6 months	High MP (3.6 g/ring); Low MP (1.8 g/ring)	Vaginal E2 ring (0.36 g/ring)	Yes: baseline, 1, 2, 4, 6 months	Yes: if endometrial thickness >6.5 mm (n = 6)	Endometrial thickness increased in 20.7% (7.7–9.5 mm); histology: atrophic in 4/6 samples, secretory in 1/6 samples, polyp in 1/6 samples, no hyperplasia
Ross^39	RCT	31/24	3 months	Group 1: 45 mg vaginal; group 2: 90 mg vaginal MP every 48 h	CEE oral 0.625 mg/day	No	Yes: baseline, 1 cycle, 3 cycles (each 2nd cycle phase)	Histology after 3 cycles in group 1: atrophic in 2/11, early secretory in 6/11, late secretory in 2/11; in group 2: atrophic in 1/13, early secretory in 9/13, late secretory in 2/13; no hyperplasia or proliferative endometrium
Noe^34	RCT	44/42	12 weeks	MP vaginal ring: group 1: 0.5 (5 mg/day) or group 2: 1 g (10 mg/day)	Transdermal E2 50 μg/day	Yes: baseline, 12 weeks	Yes: baseline, 12 weeks	Endometrial thickness in group 1: 3.0 > 4.5 mm, group 2: 3.2 > 4.8 mm (significant increase in both groups, no comparison between groups) Histology in group 1: atrophic in 14/21, insufficient in 1/21, proliferative in 6/21; in group 2: atrophic in 15/21, insufficient in 2/21, proliferative in 3/21(non-significant)
Ferrero^38	RCT	60/60	1 year	Group 1: MPA oral 10 mg/day for 12 days/month; group 2: NETA transdermal 0.25 mg/day for 14 days; group 3: MP vaginal 100 mg/day 12 days/month	E2 transdermal 50 μg/day	No	Yes: baseline, 6, 12 months (always including hysteroscopy)	Histology in MPA group: atrophic in 13/20, proliferative in 4/20, hyperplastic in 1/20, secretory in 2/20; in NETA group: atrophic in 11/20, proliferative in 5/20, hyperplastic in 3/20, secretory in 1/20, simple hyperplasia in 1/20; in MP group: atrophic in 9/20, proliferative in 2/20, hyperplastic in 2/20, secretory in 7/20
Antoniou^27	RCT	56/56	12 months	Group 1: vaginal MP 100 mg/day for 7 days/month; group 2: LNG-IUD (20 μg/day)	Group 1: vaginal E2 ring for 3 months (2 mg); group 2: transdermal E2 50 μg/day	Baseline, 1 year	Baseline, 1 year	Endometrial thickness: group 1 2.9 mm >2.6 mm, group 2 3.0 mm >2.8 mm Histology: group 1: atrophic in 27/28 samples, insufficient in 1/28 samples; group 2: atrophic in 20/28 samples, insufficient in 1/28 samples, no proliferation
Cicinelli^37	Prospective cohort trial	9	4 weeks	Vaginal MP 100 mg/day for 10 days/month	Transdermal E2 100 μg/day	No	After 4 weeks	Secretory endometrium (all samples)
Di Carlo^5	Open-label RCT	100/80	12 menstrual cycles	Group A: oral MP 100 mg/day; group B: oral MP 200 mg/day; group C: vaginal MP 100 mg/day; group D: vaginal MP 200 mg/day; sequential regimen (14–25th cycle days/28-day cycle)	Transdermal E2 50 μg/day	Yes: baseline, end of study (after progestogen withdrawal bleeding)	No	Endometrial thickness: no significant group differences at baseline and after 12 menstrual cycles; significant increase of endometrial thickness when comparing baseline with after 12 cycles for groups A–C (but <6 mm in all cases)
de Ziegler^29	Non-randomizedprospective trial	136	6 months	Group 1: MP vaginal 45 mg/day for 10 days/month; group 2: MP vaginal 45 mg 2/week	Estrogens (oral E2 valerate 2 mg/day, oral CEE 0.625 mg/day; transdermal E2 50 μg/day)	Yes: baseline, 6, 18 months	Yes, but only if abnormal uterine bleeding and/or endometrial thickness >10 mm	Endometrial thickness: group 1 5.1 > 4.9 mm; group 2: not given. Histology (n not given): no hyperplasia or cancer
Fernandez-Murga^30	Non-randomizedprospective trial	64/27	1 year	MP 100 mg 2/week	E2 transdermal 2 μg/day	Yes: baseline, 6, 12 months	Yes, if abnormal bleeding occurred	Endometrial thickness: 2.9 mm >3.5 mm (non-significant). Histology: atrophy in all (n = 7)
Cicinelli^31	Prospective observational trial	35/26	1 year	Vaginal P4 45 mg 2/week	E2 transdermal 50 μg/day	Yes: baseline, 12 months	Yes: baseline, 12 months	Endometrial thickness: 3.6 mm >4.6 mm (significant). Histology: at baseline all atrophy, at 12 months atrophy in 92.3%
Miles^32	Non-randomizedprospective trial	20 postmenopausal, 4 premenopausal women	21 days	Group 1: vaginal P4 200 mg every 6 h, starting on cycle day 15; group 2: intramuscular P4 50 mg 2/day	Increasing E2 dosages for oocyte donation	Yes: cycle day 21	Yes: cycle day 21	Endometrial thickness: 11.4 mm (group 1) and 11.1 mm (group 2). Histology: no difference between groups
Cicinelli^33	Prospective trial	30/23	3 years	Vaginal P4 100 mg every other day	Transdermal E2 1.5 mg/day	Yes: baseline, every 6 months	Yes: After 3 years	Endometrial thickness: 3.4 mm >2.7 mm (3 years). Histology: atrophy in all cases
Suvanto-Luukkonen^35	Non-randomizedprospective trial	60/51	1 year	Group 1: LNG-IUD; group 2: oral MP 100 mg/day; group 3: MP 100–200 mg/day vaginal for 25 days/month	E2 transdermal 1.5 mg/day	Yes: baseline, 3, 6, 12 months	Yes: baseline, 12 months	Endometrial thickness: group 1: 2.0 > 3.0 mm; group 2: 2.4 > 2.7 mm; group 3: 2.5 > 2.4 mm (non-significant change within groups). Histology: group 1: atrophy in 12/18, inactive in 5/18; group 2: inactive in 4/19, partly proliferative in 5/19, mostly proliferative in 8/19, secretory in 1/19; group 3: inactive in 5/14, partly proliferative in 1/14, mostly proliferative in 7/14, secretory in 1/14
Suvanto-Luukkonen^23	Non-randomizedprospective trial	30/27	24 months	Group 1: LNG-IUD (20 μg/day); group 2: oral MP 200 mg/day for 25 days per calendar month; group 3: vaginal 100–200 mg/day on 25 days per calendar month	Transdermal E2 1.5 mg/day	No	Yes: baseline, 12–24 months	Histomorphology at baseline: atrophic in 10/14, mild proliferation in 3/14, inactive in 1/14; for LNG at month 24: atrophic in 15/16, partly proliferative in 1/16; for oral MP at month 24: proliferative in 9/10, inactive in 1/10; for vaginal MP at month 24: inactive in 3/3
Vilodre^36	Open, uncontrolled prospective trial	20/20	1 year	MP vaginal 100 mg/day for 21/28 days	E2 1.5 mg/day for 21/28 days	Yes: baseline, 1 year	Yes: baseline, 1 year	Endometrial thickness unchanged. Histology after 12 months: atrophy in 11/20, proliferative or secretory pattern in 9/20

a , recruited/analyzed; ^b, measured by transvaginal ultrasound

RCT, randomized controlled trial; CEE, conjugated equine estrogen; E2, 17β-estradiol; MPA, medroxyprogesterone acetate; NETA, norethisterone acetate; P4, progesterone; LNG-IUD, levonorgestrel-releasing intrauterine device

Table 4. Overview of trials investigating menopausal hormone therapy (MHT) containing transdermal micronized progestin (MP).

					Dosage and application regimen		Endometrium
Reference	Study design	Sample size^a	Study duration	Reproductivestage^c	Progestogen	Estrogen	Thickness^b	Histology (biopsy)	Results
Leonetti^41	PC-RCT	37/32	28 days	Post	Transdermal MP cream; 2×/day at 0%, 1.5% or 4.0% (based on patient’s weight)	Oral CEE 0.625 mg/day	No	Yes: pre and post MP application. Histology: 0, inactive; 1, scantly proliferative; 2, moderately proliferative; 3, proliferative; 4, highly proliferative. Endpoint: EPS by ranking all slides relative to each other	Significant EPS reduction by 1.5% and 4.0% MP cream compared to pre-treatment with estrogens
Wren^44^,^45	RCT	27/21	12 weeks	Post	Transdermal MP cream at 16 mg/day (n = 9) or 32 mg/day (n = 8) or 64 mg/day (n = 10) for 14 days/cycle (sequential)	Transdermal E2 patch 100 μg/day	No	Yes: pre and post MP application	At BL, n = 6 proliferative; at week 48, n = 19 proliferative (results for groups not given)
Leonetti^42	Unblindedcross-over RCT	33/26	6 months pertreatment arm	Post	Transdermal MP cream 40 mg/day (continuous) or oral MPA 2.5 mg/day (continuous)	Oral CEE 0.625 mg/day	No	Yes: pre and post MP/MPA application	Histology in MP cream group: atrophic in 81%, proliferative in 19%; histology in oral MPA group: atrophic in 73%, proliferative in 27%; no hyperplasia
Vashisht^43	Open-label singlearm study	54/41	48 weeks	Post	Transdermal MP cream 40 mg/day (continuous)	Transdermal E2 cream 1 mg/day	Yes: pre andpost MHT	Yes: pre and post MHT	Endometrial thickness: significant increase from mean 3.3 mm to mean 5.3 mm; Histology at BL: 100% atrophic or insufficient; histology at week 48: atrophic in 29%, secretory in 8%, proliferative in 26%, complex hyperplasia (± atypia) in 5%

a , recruited/analyzed; ^b, measured by transvaginal ultrasound; ^c, post, postmenopause.

PC-RCT, Placebo-controlled, randomized controlled trial; RCT, randomized controlled trial; CEE, conjugated equine estrogen; E2; 17β-estradiol; MPA, medroxyprogesterone acetate; EPS, endometrial proliferation score; BL, baseline

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