Impact of vaginal estriol on serum hormone levels: a systematic review

Figures & data

Figure 1. Flow diagram of the selection and assessment of the studies.

Table 1. Effects of vaginal estriol (E3) on serum E3 levels.

Study (authors and year)	Study design	Study cohort (n)	Cohort characteristics	Intervention/control (dose, form, duration)	Type of comparison, measurement methodology	E3 (A)	E3 (B)	E3 (C)
Mattsson and Cullberg (1983) [24]	Multi-arm pre–post interventional studies	Total: 30 patients (3 withdrawn) A: 14 B: 13	A: mean age 59.5 years B: mean age 58.0 years	A: 0.5 mg E3/day for 14 days + 2×/week for 6 weeks (Ovestin^® vaginal cream) B: 0.5 mg E3/day for 14 days + 2×/week for 6 weeks (Ovestin^® vaginal suppositories)	Pre vs. post comparison (mean ± SE) 0 weeks, 2 weeks (20 h after last E3) Radioimmunoassay	0 weeks (unconjugated): <0.05 nmol/l 2 weeks (unconjugated): 0.23 ± 0.08 nmol/l, p < 0.001 0 weeks (conjugated): 0.28 ± 0.01 nmol/l 2 weeks (conjugated): 1.48 ± 0.2 nmol/l, p < 0.001	0 weeks (unconjugated): <0.05 nmol/l 2 weeks (unconjugated): 0.11 ± 0.02 nmol/l 0 weeks (conjugated): 0.33 ± 0.05 nmol/l 2 weeks (conjugated): 1.57 ± 0.2 nmol/l, p < 0.001
Luisi et al. (1980) [9]	Controlled trial	Total: 14 patients A: 7 B: 7	Participants between 53 and 65 years No further data available	A: 0.5 mg E3/day for 3 weeks (Ovestin^® vaginal cream) B: 1.25 mg CEE/day for 3 weeks (Premarin^® vaginal cream)	A vs. B (mean) 0 days, 8 days, 15 days, 21 days (morning) Radioimmunoassay	0 days: <12 pg/ml 8 days: 15 days: 21 days: 23.4 pg/ml	0 days: <12 pg/ml 8 day: 15 days: 21 days: 23.9 pg/ml
Sánchez‐Rovira et al. (2020) [10] / Hirschberg et al. (2020) [11]	Controlled trial	Total: 61 patients A: 50 B:11	A: mean age 58.9 years B: mean age 61.4 years	A: 50 μg E3/day for 3 weeks + 2×/week for 9 weeks (Blissel^®, Gelistrol^®, Gelisse^® vaginal gel) B: moisturizer 1×/day for 3 weeks + 2×/week for 9 weeks (Ainara^® vaginal gel)	Pre vs. post comparison (median + Δ: physiological variability vs. treatment variability) 0 weeks, 1 weeks, 3 weeks, 8 weeks, 12 weeks Liquid chromatography with tandem mass spectrometry	0 weeks: <0.5 pg/ml (below limit of quantitation) 1 week: 3.9 pg/ml (median) 3 weeks: 1.9 pg/ml (median) 8 weeks: <0.5 pg/ml (below limit of quantitation) 12 weeks: <0.5 pg/ml (below limit of quantitation)	0 weeks: <0.5 pg/ml (below limit of quantitation) 1 week: <0.5 pg/ml (below limit of quantitation) 3 weeks: <0.5 pg/ml (below limit of quantitation) 8 weeks: <0.5 pg/ml (below limit of quantitation) 12 weeks: <0.5 pg/ml (below limit of quantitation)
Wesel et al. (1981) [12]	Single-arm pre–post interventional study	Total: 50 patients A: only 15 for the outcome of interest	A: mean age 61.76 years	A: 0.5 mg E3/day for 3 weeks + 2×/week for 4 weeks (Ortho-Gynest^® vaginal pessaries)	Blood samples: 0 weeks, 1 week, 3 weeks, 5 weeks, 7 weeks Radioimmunoassay	Values individually given for each participant (calculated means/median) 0 days: mean <25.4 pg/ml | median: <25 pg/ml 7 days: mean <40.4 pg/ml | median: 26 pg/ml 21 days: mean <37.5 pg/ml | median: <25 pg/ml 35 days: mean <27.0 pg/ml | median: <25 pg/ml 49 days: mean <27.7 pg/ml | median: <25 pg/ml
Te West et al. (2020) [13]	Multi-arm pre–post interventional studies	Total: 76 patients (90 recruited) A: 27 (40 recruited, 13 withdrew) | a: 10, b: 10, c: 20 B: 49 (50 recruited, 1 excluded)	A: mean age 66.6 years (A = new users) B: median age 75.5 years (B = chronic users, >3 months)	Aa: 0.5 mg E3/day for 3 weeks + 2×/week for 9 weeks (Ovestin^® vaginal cream with applicator) Ab: 0.5 mg E3/day for 3 weeks + 3×/week for 9 weeks (Ovestin^® vaginal cream, digitally, measured) Ac: 0.5 mg E3/day for 3 weeks + 3×/week for 9 weeks (Ovestin^® vaginal cream, digitally, free) B: 0.5 mg E3 2–3×/week for 9 weeks (Ovestin^® vaginal cream)	Median (IQR) – Aa, Ab, Ac analyzed as one group Blood samples: 0 weeks, 2 weeks (12 h after last E3) Liquid chromatography with tandem mass spectrometry	0 weeks: <5.0 pmol/l 2 weeks: <22.8 pmol/l (9.2–108.5)	2 weeks: 15.1 pmol/l (2.7–33.9)
Haspels et al. (1981) [15]	Single-arm pre–post interventional study	Total: 11 patients A: 11	A: between 54 and 70 years (no further information provided)	A: 0.5 mg E3/day for 3 weeks + 2×/week for 5 weeks (Ovestin^® vaginal cream)	Pre vs. post (mean ± SD) Blood samples: 0 days, 21 days, 35 days, 56 days (ca. 10–12 h after application) Radioimmunoassay	0 days: <35.0 pmol/l 21 days: 86.8 ± 8.1 pmol/l 35 days: 68.2 ± 6.3 pmol/l 56 days: 60.4 ± 10.1 pmol/l E3 rose from undetectable to a mean baseline of 86.8 at day 21
de Oliveira Filho et al. (2019) [25]	Controlled trial	Total: 31 patients A: 10 B: 10 C: 11	A: mean age 56.1 years B: mean age 55.9 years C: mean age 55.5 years	A: 0.125 mg E3/day for 21 days (single 100 mg vaginal ring) B: 0.250 mg E3/day for 21 days (single 300 mg vaginal ring) C: 0.500 mg E3/day for 21 days (single 600 mg vaginal ring)	Pharmacokinetic/dynamics Liquid chromatography with tandem mass spectrometry	Cday 21: 7 pg/ml Cmax: 68 pg/ml @ t = 2 h Cav: 25 pg/ml Clear dose dependency – Cmax increase with dose was less than proportional	Cday 21: 6 pg/ml Cmax: 97 pg/ml @ t = 5 h Cav: 38 pg/ml Clear dose dependency – Cmax increase with dose was less than proportional	Cday 21: 10 pg/ml Cmax: 155 pg/ml @ t = 9 h Cav: 59 pg/ml Clear dose dependency – Cmax increase with dose was less than proportional
Delgado et al. (2016) [26]	Controlled trial	Total: 43 patients A: 13 B: 12 C: 12 D: 6	A: mean age 57.4 years B: mean age 59.6 years C: mean age 57.8 years D: mean age 62.7 years	A: 0.002% E3/day for 21 days (vaginal gel) B: 0.005% E3/day for 21 days (vaginal gel) C: 0.1% E3/day for 21 days (Ovestinon^® vaginal cream) D: placebo for 21 days (vaginal gel)	Pre vs. post and among groups (E3 mean, FSH/LH median) Blood samples: 1 days, 21 days Liquid chromatography with tandem mass spectrometry	A 1 day vs. 21 days: statistically significant (lower), p = 0.0006 1 day A vs. B: statistically significant different, p = 0.0043	B 1 day vs. 21 days: statistically significant (lower), p = 0.0004 21 days A vs. B: no statistically significant difference	C 1 day vs. 21 days: not statistically significant change 1 day A/B vs. C: statistically significant (higher), p ≤ 0.0005 21 days A/B vs. C: statistically significant (higher), p = 0.0004
Te West et al. (2021) [18]	Single-arm pre–post interventional study	Total: 10 patients A: 10	A: mean age 70.0 years Chronic users	A: chronic usage omitted for ≥36 h prior to the study, then 0.5 mg E3 once (Ovestin^® vaginal cream)	Pre vs. post (mean (SE)) Blood samples: 0 h, 1 h, 2 h, 3 h, 5 h, 8 h, 10 h, 12 h, 24 h Liquid chromatography with tandem mass spectrometry	0 h: 5 pmol/l (1.7) 1 h: 317 pmol/l (65.4) 2 h: 505 pmol/l (81.9) 3 h: 455 pmol/l (78.4) 5 h: 296 pmol/l (62.5) 8 h: 69 pmol/l (19.7) 10 h: 36 pmol/l (11.8) 12 h: 19 pmol/l (7.0) 24 h: 7 pmol/l (3.5) Cmax(mean): 546 pmol/l (SD 310) @ t = 2.3 h	E3 was absorbed rapidly and the decline in serum concentrations was rapid At 24 h all women had E3 levels <30 pmol/l
Rueda et al. (2017) [19]	Systematic review	Total: 22 articles – Studying E3: 20 – Studying E3 and serum hormones: 11 studies (4 already included [14,19,23] − 1 excluded based on our criteria since combination E3/P4 studied − 6 not separately included) a) Batra and Iosif (1987) [28] b) Keller et al. (1981) [29] c) Heimer and Englund (1984) [30] d) Punnonen et al. (1980) [32] e) Mattsson and Cullberg (1983) [33] f) Heimer and Englund (1986) [31]	a: (Controlled trial) 17 patients (10 E3 vs. 7 no treatment) b: (Pre–post interventional study) 3 patients c: (Pre–post interventional study) 6 patients d: (Controlled trial) 10 patients (5 E3) e: (Controlled trial) 8 patients f: (Pre–post interventional study) 9 patients	a: 1 mg E3 ovula 14 h pre and 1 h post-OP for uterine prolapse b: 0.5 mg E3 for 10 days (ovula) c: 1 mg E3 for 21 days (ovula) d: 2.4 mg CEE vs. 2 mg E2 vs. 0.5 mg E3 for 24 h e: 0.5 mg E3 cream or ovula for 14 days (time comparison) f: 0.5 mg E3 for 21 days	Radioimmunoassay – most studies	a – pre: 10 pg/ml, post: 50 mg/ml b – 0 h: 40 pg/ml | 1 h: 1290 pg/ml | 2 days: 123 pg/ml | 10 days: 293 pg/ml c – 0 days: 9133 AUC | 21 days: 6743 AUC, p = 0.05 d – 0 h: 0.15 nmol/l | 2 h: 0.4 nmol/l | 8 h: <0.10 nmol/l, 12 h: 0.09 nmol/l | 24 h: <0.05 nmol/l, p = 0.05 e – cream and unconjugated E3, 0 h: 0 | 30 months: 0.3 nmol/l (p = 0.05) | 2 h: 0.61 ± 0.11 nmol/l (p = 0.01) | 24h: baseline levels – cream and conjugated E3, 0 h: 0.3 nmol/l | 4 h: 1.33 ± 0.17 nmol/l (p < 0.01) | 48 h: baseline levels – ovula and unconjugated E3, 0 h: 0 | 30 months: 0.3 nmol/l (p = 0.05) | 1 h: 0.51 ± 0.24 nmol/l (p = 0.01) | 24 h: baseline levels – ovula and conjugated E3, 0 h: 0.29 nmol/l | 8 h: 1.43 ± 0.33 nmol/l (p < 0.01) | 48 h: baseline levels f – AUC 0–12 h: morning 5943 | evening 4713.5 AUC 0–24 h: morning 9941 | evening 8722.5
Kicovic et al. (1980) [20]	Controlled trial	Total: 74 patients (32 for serum studies) A: 23 (17 serum studies) B: 30 (10 serum studies) C: 21 (5 serum studies)	Ages between 44 and 82 years (no further information provided)	A: 1 mg E3/day for 3 weeks + subgroup further 2×/week for 13 weeks (Ovestin^® vaginal cream) B: 0.5 mg E3/day for 3 weeks + subgroup further 2×/week for 13 weeks (Ovestin^® vaginal cream) C: 0.5 mg E3/day for 2 weeks (Ovestin^® vaginal suppositories)	Blood samples: 1 day (0 h, 1 h, 2 h, 3 h, 4 h, 6 h) and 21 days (A and B) or 15 days (C) – 12 h after last dose (=0 h and 1 h, 2 h, 3 h, 4 h, 6 h) Radioimmunoassay	1 day, 0 h (unconjugated): <12 pg/ml 1 day, 1 h: 123.6 pg/ml (mean peak value) 1 day, 1–5 h: gradual decline 21 days, 0 h: 26 pg/ml 21 days, 1 h: 104.9 pg/ml (mean peak value) 21 days, 1–5 h: gradual decline	1 day, 0 h (unconjugated): <12pg/ml 1 day, 1 h: 110.8 pg/ml (mean peak value) 1 day, 1–5 h: gradual decline 21 days, 0 h: 26 pg/ml 21 days, 1 h: 95.0 pg/ml (mean peak value) 21 days, 1–5 h: gradual decline	1 day, 0 h (unconjugated): <12pg/ml 1 day, 2 h: 92.6/ml (mean peak value) 1 day, 2–5 h: gradual decline 15 days, 0 h: 30.8 pg/ml 15 days, 2 h: 92.8 pg/ml (mean peak value) 15 days, 2–5 h: gradual decline
Donders et al. (2014) [21]	Single-arm pre–post interventional study	Total: 16 patients A: 16	A: mean age 57.0 years	A: 0.03 mg E3/day for 4 weeks + 3×/week for 8 weeks (Gynoflor^® vaginal tablets)	Pre vs. post (mean (SD)) Blood samples: 0 days and 28 days; 0 h, 0.5 h, 1 h, 3 h, 2 h, 4 h, 6 h, 8 h, 24 h Gas chromatography–mass spectrometry	Day 0 (A Group) [LLOQ set 10.00 pg/ml] 0 days, 0 h: LLOQ (0) 0 days, 0.5 h: 3.83 pg/ml (5.74) 0 days, 1 h: 11.04 pg/ml (6.66) 0 days, 2 h: 72.73 pg/ml (49.11) 0 days, 3 h: 84.35 pg/ml (43.77) 0 days, 4 h: 28.29 pg/ml (18.64) 0 days, 6 h: LLOQ (0) 0 days, 8 h: LLOQ (0) 0 days, 24 h: LLOQ (0) 0 days Cmax: 168 pg/ml @ t = 3 h 0 days mean Cmax: 104.5 pg/ml (40.9), 2.5 h	Day 28 (A Group) 28 days, 0 h: 0.91 pg/ml (3.51) 28 days, 0.5 h: 1.58 pg/ml (4.05) 28 days, 1 h: 1.55 pg/ml (4.16) 28 days, 2 h: 1.96 pg/ml (5.20) 28 days, 3 h: 2.48 pg/ml (7.35) 28 days, 4 h: 3.12 pg/ml (9.40) 28 days, 6 h: 7.33 pg/ml (12.26) 28 days, 8 h: 10.23 pg/ml (12.33) 28 days, 24 h: LLOQ (0) 28 days Cmax: 43.7 pg/ml @ t = 8 h, p < 0.0001 28 days mean Cmax: 15.8 pg/ml (13.9), 7.2 h	Mean E3 values 0 days: 0.00 (0) 14 days: 5.11 pg/ml (14.01) 28 days: 0.91 pg/ml (3.63) 56 days: 0.00 (0) 84 days: 0.00 (0)
Pfeiler et al. (2011) [22]	Single-arm pre–post interventional study	Total: 10 patients A: 10	A: median age 65.0 years	A: 0.5 mg E3/day for 2 weeks (Ovestin^® vaginal tablets)	Pre vs. post comparison (mean) 0 weeks, 2 weeks (8–12 h after E3) Gas chromatography–mass spectrometry	0 weeks: <0.2 ng/ml 2 weeks: <0.2 ng/ml
Buhling et al. (2012) [27]	Single-arm pre–post interventional study	Total: 19 patients A: 19	A: mean age 62.7 years	A: 0.03 mg E3/day for 21 days (OeKolp^® vaginal pessaries)	Pre vs. post (mean) Blood samples: 1 day (after first administration); 6 days, 11 days, 16 days (predose); 21 days (after last administration) Liquid chromatography with tandem mass spectrometry	1 day, 1 h: 42.1 pg/ml (max mean plasma concentration) 1 day, 12 h: <5.0 pg/ml (LLOQ) in all patients Repeated administration did not result in an accumulation of estriol 21 days, 2 h: 11.9 pg/ml (max mean plasma concentration) Very low systemic bioavailability, which decreased even more after multiple dosing confirming a favorable safety profile of low dose pessaries administered daily over 21 days

The meta-analysis of Pavlović et al. [23] is not included in the table since the results of all included studies are separately presented. AUC, area under the curve; CEE, conjugated equine estrogens; FSH, follicle stimulating hormone; IQR, interquartile range; LH, luteinizing hormone; LLOQ, lower limit of quantitation. A, B, C refer to the groups within each study and the respective treatment and outcomes for each. The statistically significant results (p<0.05) appear in bold.

Table 2. Effects of vaginal estriol (E3) on serum estradiol (E2) levels.

Study (authors and year)	Study design	Study cohort (n)	Cohort characteristics	Intervention/control (dose, form, duration)	Type of comparison	E2 (A)	E2 (B)	E2 (C)
Luisi et al. (1980) [9]	Controlled trial	Total: 14 patients A: 7 B: 7	Participants between 53 and 65 years No further data available	A: 0.5 mg E3/day for 3 weeks (Ovestin^® vaginal cream) B: 1.25 mg CEE/day for 3 weeks (Premarin^® vaginal cream)	A vs. B (mean) 0 days, 8 days, 15 days, 21 days (morning)	0 days: ? 8 days: ? (no effect) 15 days: ? (no effect) 21 days: ? (no effect)	0 days: 26.3 pg/ml 8 days: ?, p < 0.05 (A vs. B) 15 days: ?, p < 0.05 (A vs. B) 21 days: 139.2 pg/ml p < 0.05 (A vs. B)
Sánchez‐Rovira et al. (2020) [10] / Hirschberg et al. (2020) [11]	Controlled trial	Total: 61 patients A: 50 B: 11	A: mean age 58.9 years B: mean age 61.4 years	A: 50 μg E3/day for 3 weeks + 2×/week for 9 weeks (Blissel^®, Gelistrol^®, Gelisse^® vaginal gel) B: moisturizer 1×/day for 3 weeks + 2×/week for 9 weeks (Ainara^® vaginal gel)	Pre vs. post comparison (median + Δ: physiological variability vs. treatment variability) 0 weeks, 1 week, 3 weeks, 8 weeks, 12 weeks	0 weeks: <1.5 pg/ml (below limit of quantitation) 1 week: <1.5 pg/ml (below limit of quantitation) 3 weeks: <1.5 pg/ml (below limit of quantitation) 8 weeks: <1.5 pg/ml (below limit of quantitation) 12 weeks: <1.5 pg/ml (below limit of quantitation)	0 weeks: <1.5 pg/ml (below limit of quantitation) 1 week: <1.5 pg/ml (below limit of quantitation) 3 weeks: <1.5 pg/ml (below limit of quantitation) 8 weeks: <1.5 pg/ml (below limit of quantitation) 12 weeks: <1.5 pg/ml (below limit of quantitation)
Wesel et al. (1981) [12]	Single-arm pre–post interventional study	Total: 50 patients A: only 15 for the outcome of interest	A: mean age 61.76 years	A: 0.5 mg E3/day for 3 weeks + 2×/week for 4 weeks (Ortho-Gynest^® vaginal pessaries)	Blood samples: 0 weeks, 1 week, 3 weeks, 5 weeks, 7 weeks	No change, always remained <30 pg/ml for the majority of patients
Te West et al. (2020) [13]	Multi-arm pre–post interventional studies	Total: 76 patients (90 recruited) A: 27 (40 recruited, 13 withdrew) | a: 10, b: 10, c: 20 B: 49 (50 recruited, 1 excluded)	A: mean age 66.6 years (A = new users) B: median age 75.5 years (B = chronic users, >3 months)	Aa: 0.5 mg E3/day for 3 weeks + 2×/week for 9 weeks (Ovestin^® vaginal cream with applicator) Ab: 0.5 mg E3/day for 3 weeks + 3×/week for 9 weeks (Ovestin^® vaginal cream, digitally, measured) Ac: 0.5 mg E3/day for 3 weeks + 3×/week for 9 weeks (Ovestin^® vaginal cream, digitally, free) B: 0.5 mg E3 2–3×/week for 9 weeks (Ovestin^® vaginal cream)	Median (IQR) – Aa, Ab, Ac analyzed as one group Blood samples: 0 weeks, 2 weeks (12 h after last E3)	0 weeks: 17.0 pmol/l (9.7–26.0) 2 weeks: 16.4 pmol/l (8.3–26.0)	2 weeks: 12.8 pmol/l (6.7–18.1)
Hoz and Orozco-Gallego (2018) [14]	Controlled trial	Total: 387 patients A: 192 B: 195	A: mean age 59.0 years B: mean age 58.0 years	A: 1 mg E3/day for 2 weeks + 1×/week for total 2 years (vaginal cream) B: 0.625 mg CEE/day for 2 weeks + 1×/week for total 2 years (vaginal cream)	A vs. B (mean ± SD) 0 months, 6 months, 12 months, 18 months, 24 months	0 months: 41.4 ± 11.4 pg/ml 24 months: 52.8 ± 13.5 pg/ml	0 months: 43.2 ± 13.5 pg/ml 24 months: 54.6 ± 11.7 pg/ml
Haspels et al. (1981) [15]	Single-arm pre–post interventional study	Total: 11 patients A: 11	A: between 54 and 70 years (no further information provided)	A: 0.5 mg E3/day for 3 weeks + 2×/week for 5 weeks (Ovestin^® vaginal cream)	Pre vs. post (mean ± SD) Blood samples: 0 days, 21 days, 35 days, 56 days (ca. 10–12 h after application)	0 days: 46.2 ± 9.1 pmol/l 21 days: 49.9 ± 11.7 pmol/l 35 days: 51.0 ± 11.1 pmol/l 56 days: 52.1 ± 12.3 pmol/l Treatment did not induce changes in E2 levels
Biglia et al. (2010) [16]	Controlled trial	Total: 26 patients A: 10 B: 8 C: 8	A + B: mean age 54.1 years C: mean age 46.1 years	A: 0.25 mg E3 2×/week for 12 weeks (Colpogyn^® vaginal cream) B: 12.5 μg E2 2×/week for 12 weeks (Vagifem^® vaginal tablets) C: 2.5 g moisturizer 2×/week for 12 weeks (Replens^® vaginal cream)	A vs. B and pre vs. post for E3 (mean or score change ± SD) A + B vs. C (excluded, E2/E3 combined)	0 weeks: 14.4 ± 5.3 pg/ml 12 weeks: +3.5 ± 5.1 pg/ml	0 weeks: 19.4 ± 10.0 pg/ml 12 weeks: +2.7 ± 10.6 pg/ml	0 weeks: 27.5 ± 19.4 pg/ml
Crandall et al. (2020) [17]	Systematic review	Total: 63 articles – studying E3: 2 – studying E3 and serum hormones: 1 not separately included a) van Haaften et al. (1989) [34] – controlled trial	a: 29 patients (A: 9, B: 8, C: 12)	A: 0.05 mg E2/day for 3 weeks (vaginal ovula) B: 0.5 mg E3/day for 3 weeks (vaginal ovula) C: control (untreated)	Pre vs. post 3 weeks (mean)	Specific values not provided Levels were unchanged by either of the active treatments No results of statistical comparisons were presented	Specific values not provided Levels were unchanged by either of the active treatments No results of statistical comparisons were presented	Mean: 29 pmol/l Levels were unchanged by either of the active treatments No results of statistical comparisons were presented
Te West et al. (2021) [18]	Single-arm pre–post interventional study	Total: 10 patients A: 10	A: mean age 70.0 years Chronic users	A: chronic usage omitted for ≥36 h prior to the study, then 0.5 mg E3 once (Ovestin^® vaginal cream)	Pre vs. post (mean (SE)) Blood samples: 0 h, 1 h, 2 h, 3 h, 5 h, 8 h, 10 h, 12 h, 24 h	No evidence of a change in E2 concentrations following application of E3
Rueda et al. (2017) [19]	Systematic review	Total: 22 articles – studying E3: 20 – studying E3 and serum hormones: 11 studies (4 already included [14,19,23] − 1 excluded based on our criteria since combination E3/P4 studied − 6 not separately included) a) Batra and Iosif (1987) [28] b) Keller et al. (1981) [29] c) Heimer and Englund (1984) [30] d) Punnonen et al. (1980) [32] e) Mattsson and Cullberg (1983) [33] f) Heimer and Englund (1986) [31]	a: (Controlled trial) 17 patients (10 E3 vs. 7 no treatment) b: (Pre–post interventional study) 3 patients c: (Pre–post interventional study) 6 patients d: (Controlled trial) 10 patients (5 E3) e: (Controlled trial) 8 patients f: (Pre–post interventional study) 9 patients	a: 1 mg E3 ovula 14 h pre and 1 h post-OP for uterine prolapse b: 0.5 mg E3 for 10 days (ovula) c: 1 mg E3 for 21 days (ovula) d: 2.4 mg CEE vs. 2 mg E2 vs. 0.5 mg E3 for 24 h e: 0.5 mg E3 cream or ovula for 14 days (time comparison) f: 0.5 mg E3 for 21 days		b: no change d: no change
Kicovic et al. (1980) [20]	Controlled trial	Total: 74 patients (32 for serum studies) A: 23 (17 serum studies) B: 30 (10 serum studies) C: 21 (5 serum studies)	Ages between 44 and 82 years (no further information provided)	A: 1 mg E3/day for 3 weeks + subgroup further 2×/week for 13 weeks (Ovestin^® vaginal cream) B: 0.5 mg E3/day for 3 weeks + subgroup further 2×/week for 13 weeks (Ovestin^® vaginal cream) C: 0.5 mg E3/day for 2 weeks (Ovestin^® vaginal suppositories)	Blood samples: 1 day (0 h, 1 h, 2 h, 3 h, 4 h, 6 h) and 21 days (A and B) or 15 days (C) – 12 h after last dose (=0 h and 1 h, 2 h, 3 h, 4 h, 6 h)	1 day: ? 21 days: unaffected	1 day: ? 21 days: unaffected	1 day: ? 15 days: unaffected
Donders et al. (2014) [21]	Single-arm pre–post interventional study	Total: 16 patients A: 16	A: mean age 57.0 years	A: 0.03 mg E3/day for 4 weeks + 3×/week for 8 weeks (Gynoflor^® vaginal tablets)	Pre vs. post (mean (SD)) Blood samples: 0 days and 28 days; 0 h, 0.5 h, 1 h, 3 h, 2 h, 4 h, 6 h, 8 h, 24 h	No increase, always under LLOQ (1.00 pg/ml) both 0 days and 28 days
Pfeiler et al. (2011) [22]	Single-arm pre–post interventional study	Total: 10 patients A: 10	A: median age 65.0 years	A: 0.5 mg E3/day for 2 weeks (Ovestin^® vaginal tablets)	Pre vs. post comparison (mean) 0 weeks, 2 weeks (8–12 h after E3)	0 weeks: <10 pg/ml 2 weeks: <10 pg/ml

The meta-analysis of Pavlović et al. [23] is not included in the table since the results of all included studies are separately presented. CEE, conjugated equine estrogens; IQR, interquartile range; LLOQ, lower limit of quantitation. A, B, C refer to the groups within each study and the respective treatment and outcomes for each. The statistically significant results (p<0.05) appear in bold.

Table 3. Effects of vaginal estriol (E3) on serum gonadotropin (FSH and LH) levels.

Study (authors and year)	Study design	Study cohort (n)	Cohort characteristics	Intervention/control (dose, form, duration)	Type of comparison	FSH (A)	FSH (B)	FSH (C)	LH (A)	LH (B)	LH (C)
Mattsson and Cullberg (1983) [24]	Multi-arm pre–post interventional studies	Total: 30 patients (3 withdrawn) A: 14 B: 13	A: mean age 59.5 years B: mean age 58.0 years	A: 0.5 mg E3/day for 14 days + 2×/week for 6 weeks (Ovestin^® vaginal cream) B: 0.5 mg E3/day for 14 days + 2×/week for 6 weeks (Ovestin^® vaginal suppositories)	Pre vs. post comparison (mean ± SE) 0 weeks, 2 weeks (20 h after last E3)	0 weeks: 14.2 ± 0.4 μg/l 2 weeks: 13.5 ± 0.4 μg/l, p < 0.01	0 weeks: 14.9 ± 0.7 μg/l 2 weeks: 13.7 ± 0.6 μg/l, p < 0.05		0 weeks: 9.2 ± 0.5 μg/l 2 weeks: 8.0 ± 0.6 μg/l	0 weeks: 10.3 ± 0.9 μg/l 2 weeks: 11.6 ± 1.0 μg/l
Luisi et al. (1980) [9]	Controlled trial	Total: 14 patients A: 7 B: 7	Participants aged between 53 and 65 years No further data available	A: 0.5 mg E3/day for 3 weeks (Ovestin^® vaginal cream) B: 1.25 mg CEE/day for 3 weeks (Premarin^® vaginal cream)	A vs. B (mean) 0 days, 8 days, 15 days, 21 days (morning)	0 days: 75.2 mIU/ml 8 days: ? 15 days: ? 21 days: 70.5 mIU/ml	0 days: 71.0 mIU/ml 8 days: ?, p < 0.05 (A vs. B) 15 days: ?, p < 0.05 (A vs. B) 21 days: 55.6 mIU/ml, p < 0.05 (A vs. B)		0 days: 59.3 mIU/ml 8 days: ? 15 days: ? 21 days: 53.1 mIU/ml	0 days: 57.6 mIU/ml 8 days: ?, p < 0.05 (A vs. B) 15 days: ?, p < 0.05 (A vs. B) 21 days: 44.4 mIU/ml, p < 0.05 (A vs. B)
Sánchez‐Rovira et al. (2020) [10] / Hirschberg et al. (2020) [11]	Controlled trial	Total: 61 patients A: 50 B: 11	A: mean age 58.9 years B: mean age 61.4 years	A: 50 μg E3/day for 3 weeks + 2×/week for 9 weeks (Blissel^®, Gelistrol^®, Gelisse^® vaginal gel) B: moisturizer 1×/day for 3 weeks + 2×/week for 9 weeks (Ainara^® vaginal gel)	Pre vs. post comparison (median + Δ: physiological variability vs. treatment variability) 0 weeks, 1 week, 3 weeks, 8 weeks, 12 weeks	0 weeks: 54.6 mIU/ml 1 week: 47.6 mIU/ml, Δ = −4.8, p < 0.05 3 weeks: 48.7 mIU/ml, Δ = −4.2, p < 0.05 8 weeks: 51.4 mIU/ml, Δ = −2.6 12 weeks: 51 mIU/ml, Δ = −2.8	0 weeks: 47.6 mIU/ml 1 week: 53.8 mIU/ml, Δ = +4.2 3 weeks: 65.1 mIU/ml, Δ = −0.9 8 weeks: 55.7 mIU/ml, Δ = +5.2 12 weeks: 62.1 mIU/ml, Δ = +1.4		0 weeks: 19.8 mIU/ml 1 week: 18.2 mIU/ml, Δ = −0.6 3 weeks: 19.6 mIU/ml, Δ = −0.5 8 weeks: 17.7 mIU/ml, Δ = −0.3 12 weeks: 19.3 mIU/ml, Δ = −0.8	0 weeks: 25.3 mIU/ml 1 week: 30.1 mIU/ml, Δ = +0.2 3 weeks: 28.7 mIU/ml, Δ = +0.3 8 weeks: 27.8 mIU/ml, Δ = −1.3 12 weeks: 28.9 mIU/ml, Δ = +1.3
Haspels et al. (1981) [15]	Single-arm pre–post interventional study	Total: 11 patients A: 11	A: between 54 and 70 years (no further information provided)	A: 0.5 mg E3/day for 3 weeks + 2×/week for 5 weeks (Ovestin^® vaginal cream)	Pre vs. post (mean ± SD) Blood samples: 0 days, 21 days, 35 days, 56 days (ca. 10–12 h after application)	0 days: 66.0 ± 13.8 U/l 21 days: 62.8 ± 12.7 U/l 35 days: 64.9 ± 11.5 U/l 56 days: 65.8 ± 14.2 U/l FSH had a slight suppression on day 21			0 days: 48.7 ± 7.4 U/l 21 days: 45.1 ± 6.2 U/l 35 days: 46.5 ± 7.3 U/l 56 days: 47.0 ± 8.7 U/l LH had a slight suppression on day 21
Biglia et al. (2010) [16]	Controlled trial	Total: 26 patients A: 10 B: 8 C: 8	A + B: mean age 54.1 years C: mean age 46.1 years	A: 0.25 mg E3 2×/week for 12 weeks (Colpogyn^® vaginal cream) B: 12.5 μg E2 2×/week for 12 weeks (Vagifem^® vaginal tablets) C: 2.5 g moisturizer 2×/week for 12 weeks (Replens^® vaginal cream)	A vs. B and pre vs. post for E3 (mean or score change ± SD) A + B vs. C (excluded, E2/E3 combined)	0 weeks: 34.5 ± 20.6 mU/ml 12 weeks: −4.02 ± 6.9 mUI/ml	0 weeks: 62.0 ± 40.9 mU/ml 12 weeks: −2.64 ± 9. 8mUI/ml	0 weeks: 23.3 ± 24.2 mU/ml	0 weeks: 25.3 ± 19.5 mU/ml 12 weeks: −6.4 ± 13.8 mUI/ml	0 weeks: 30.5 ± 18.3 mU/ml 12 weeks: −10.6 ± 19.5 mUI/ml	0 weeks: 10.5 ± 19.4 mU/ml
de Oliveira Filho et al. (2019) [25]	Controlled trial	Total: 31 patients A: 10 B: 10 C: 11	A: mean age 56.1 years B: mean age 55.9 years C: mean age 55.5 years	A: 0.125 mg E3/day for 21 days (single 100 mg vaginal ring) B: 0.250 mg E3/day for 21 days (single 300 mg vaginal ring) C: 0.500 mg E3/day for 21 days (single 600 mg vaginal ring)	Pharmacokinetic/dynamics	0 days: 57.35 mU/ml Clear dose dependency in mean maximum decrease of FSH and rate of increase afterwards Back to baseline within second half of the treatment (only group)	0 days: 76.27 mU/ml Clear dose dependency in mean maximum decrease of FSH and rate of increase afterwards	0 days: 74.05 mU/ml Clear dose dependency in mean maximum decrease of FSH and rate of increase afterwards	0 days: 31.72 mU/ml Clear dose dependency in mean maximum decrease of LH Back to baseline within 7 days	0 days: 48.46 mU/ml Clear dose dependency in mean maximum decrease of LH Back to baseline within 7 days	0 days: 44.19 mU/ml Clear dose dependency in mean maximum decrease of LH Back to baseline within 7 days
Delgado et al. (2016) [26]	Controlled trial	Total: 43 patients A: 13 B: 12 C: 12 D: 6	A: mean age 57.4 years B: mean age 59.6 years C: mean age 57.8 years D: mean age 62.7 years	A: 0.002% E3/day for 21 days (vaginal gel) B: 0.005% E3/day for 21 days (vaginal gel) C: 0.1% E3/day for 21 days (Ovestinon^® vaginal cream) D: placebo for 21 days (vaginal gel)	Pre vs. post and among groups (E3 mean, FSH/LH median) Blood samples: 1 day, 21 days	1 day: 60.8 IU/l 21 days: 64.2 IU/l	1 day: 51.2 IU/l 21 days: 63.4 IU/l	1 day: 79.1 IU/l 21 days: 68.25 IU/l, p = 0.045 also p = 0.03 when comparing day 0–day 21 change among groups A, B, C	1 day: 28.05 IU/l 21 days: 30.05 IU/l	1 day: 26.9 IU/l 21 days: 30.8 IU/l	1 day: 35.1 IU/l 21 days: 40.4 IU/l
Crandall et al. (2020) [17]	Systematic review	Total: 63 articles – studying E3: 2 – studying E3 and serum hormones: 1 not separately included a) Van Haaften et al. (1989) [34] – controlled trial	a: 29 patients (A: 9, B: 8, C: 12)	A: 0.05 mg E2/day for 3 weeks (vaginal ovula) B: 0.5 mg E3/day for 3 weeks (vaginal ovula) C: control (untreated)	Pre vs. post 3 weeks (mean)	3 weeks mean: 38.44 IU/l No further details provided, nor between-group comparisons No results of statistical comparisons presented	3 weeks mean: 31.25 IU/l No further details provided, nor between-group comparisons No results of statistical comparisons presented	3 weeks mean: 29.00 IU/l No further details provided, nor between-group comparisons No results of statistical comparisons presented	3 weeks mean: 35.11 IU/l No further details provided, nor between-group comparisons No results of statistical comparisons presented	3 weeks mean: 43.50 IU/l No further details provided, nor between-group comparisons No results of statistical comparisons presented	3 weeks mean: 27.92 IU/l No further details provided, nor between-group comparisons No results of statistical comparisons presented
Rueda et al. (2017) [19]	Systematic review	Total: 22 articles – studying E3: 20 – studying E3 and serum hormones: 11 studies (4 already included [14,19,23] − 1 excluded based on our criteria since combination E3/P4 studied − 6 not separately included) a) Batra and Iosif (1987) [28] b) Keller et al. (1981) [29] c) Heimer and Englund (1984) [30] d) Punnonen et al. (1980) [32] e) Mattsson and Cullberg (1983) [33] f) Heimer and Englund (1986) [31]	a: (Controlled trial) 17 patients (10 E3 vs. 7 no treatment) b: (Pre–post interventional study) 3 patients c: (Pre–post interventional study) 6 patients d: (Controlled trial) 10 patients (5 E3) e: (Controlled trial) 8 patients f: (Pre–post interventional study) 9 patients	a: 1 mg E3 ovula 14 h pre and 1 h post-OP for uterine prolapse b: 0.5 mg E3 for 10 days (ovula) c: 1 mg E3 for 21 days (ovula) d: 2.4 mg CEE vs. 2 mg E2 vs. 0.5 mg E3 for 24 h e: 0.5 mg E3 cream or ovula for 14 days (time comparison) f: 0.5 mg E3 for 21 days		b: no change			b: no change
Kicovic et al. (1980) [20]	Controlled trial	Total: 74 patients (32 for serum studies) A: 23 (17 serum studies) B: 30 (10 serum studies) C: 21 (5 serum studies)	Age between 44 and 82 years (no further information provided)	A: 1 mg E3/day for 3 weeks + subgroup further 2×/week for 13 weeks (Ovestin^® vaginal cream) B: 0.5 mg E3/day for 3 weeks + subgroup further 2×/week for 13 weeks (Ovestin^® vaginal cream) C: 0.5 mg E3/day for 2 weeks (Ovestin^® vaginal suppositories)	Blood samples: 1 day (0 h, 1 h, 2 h, 3 h, 4 h, 6 h) and 21 days (A and B) or 15 days (C) – 12 h after last dose (=0 h and 1 h, 2 h, 3 h, 4 h, 6 h)	Slight suppressing effect No clinical significance	Slight suppressing effect No clinical significance	Slight suppressing effect No clinical significance	Slight suppressing effect No clinical significance	Slight suppressing effect No clinical significance	Slight suppressing effect No clinical significance
Donders et al. (2014) [21]	Single-arm pre–post interventional study	Total: 16 patients A: 16	A: mean age 57.0 years	A: 0.03 mg E3/day for 4 weeks + 3×/week for 8 weeks (Gynoflor^® vaginal tablets)	Pre vs. post (mean (SD)) Blood samples: 0 days and 28 days; 0 h, 0.5 h, 1 h, 3 h, 2 h, 4 h, 6 h, 8 h, 24 h	0 days: 107.88 mU/ml (48.62) 14 days: 103.71 mU/ml (39.76) 28 days: 98.94 mU/ml (34.95), p < 0.025 56 days: 103.55 mU/ml (37.53) 84 days: 105.93 mU/ml (43.69)			0 days: 36.46 mU/ml (11.05) 14 days: 34.52 mU/ml (12.18) 28 days: 34.02 mU/ml (12.68) 56 days: 34.2 mU/ml (49.87) 84 days: 35.13 mU/ml (10.34) No statistically significant changes
Pfeiler et al. (2011) [22]	Single-arm pre–post interventional study	Total: 10 patients A: 10	A: median age 65.0 years	A: 0.5 mg E3/day for 2 weeks (Ovestin^® vaginal tablets)	Pre vs. post comparison (mean) 0 weeks, 2 weeks (8–12 h after E3)	0 weeks: 75.7 mU/ml 2 weeks: 66.0 mU/ml, p = 0.01			0 weeks: 32.4 mU/ml 2 weeks: 28.9 mU/ml, p = 0.02

The meta-analysis of Pavlović et al. [23] is not included in the table since the results of all included studies are separately presented. CEE, conjugated equine estrogens; FSH, follicle stimulating hormone; LH, luteinizing hormone. A, B, C refer to the groups within each study and the respective treatment and outcomes for each. The statistically significant results (p<0.05) appear in bold.

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