Endometrial thickness and pathology in postmenopausal women with bleeding on transdermal 17β-estradiol plus body-identical progesterone

Abstract

Objective: The primary objective was to explore the relationship between endometrial thickness and transdermal 17β-estradiol/micronised progesterone dose in postmenopausal women with unscheduled bleeding on menopausal hormone therapy (MHT). The prevalence of endometrial pathology was also assessed.

Methods: Retrospective analysis of a consecutive case series. Postmenopausal women attending a private menopause clinic were included if they presented with unscheduled bleeding on transdermal 17β-estradiol plus micronised progesterone between 1st June 2022 and 31st May 2024, and attended for an in-house ultrasound scan.

Results: 235 women were included (mean age 57 years, 49.37% overweight or obese). 173 women (73.62%) received on-label transdermal estradiol doses. Most women (n = 220 women, 93.62%) used continuous progesterone. On ultrasound examination, 173 women (73.62%) had a normal endometrium, 48 (20.43%) had a thickened endometrium, and 14 (5.96%) had an inadequately visualised endometrium. High BMI (> 25 kg/m²) was significantly associated with increased endometrial thickness (ET) (mean ET normal BMI vs overweight: 3.84 mm vs 4.52 mm, p = 0.07; mean ET normal BMI vs obese: 3.84 mm vs 4.50 mm, p = 0.04). There was no evidence that ET differed according to transdermal estradiol dose (on- vs off-label, p = 0.53), or by progesterone dose (low vs normal vs high, p = 0.61) or route (oral vs vaginal, p = 0.26). In multivariable analyses, there was evidence of an association between ET and MHT regimen (continuous vs sequential, p = 0.03). Amongst women with a measured serum estradiol concentration (n = 92), there was no evidence of an association between ET and serum estradiol level (p = 0.21). There were no cases of endometrial hyperplasia or cancer.

Conclusions: In the study cohort, endometrial thickness in women with unscheduled bleeding on transdermal 17β-estradiol plus micronised progesterone was not associated with MHT dose. The prevalence of endometrial pathology was low, including in women using off-label estradiol doses. Our findings suggest that progesterone dose should be clinically guided for optimal efficacy and to minimise risks. More research is needed to confirm our findings and prospectively evaluate endometrial outcomes in different patient populations over longer time periods, and to enable a more personalised approach to menopause care.

Keywords: Body-identical MHT; Endometrial cancer; Endometrial pathology; Menopause; Micronised progesterone; Transdermal estradiol; Unscheduled bleeding.

Fig. 1

Flow diagram of patient outcomes. 8 patients with USB had a poorly visualised endometrium (n = 6) or thickened endometrium (n = 2) but were not referred to gynaecology (case series presented in the appendix, Table S1). 4 patients referred to gynaecology did not have a biopsy. ET endometrial thickness MHT menopausal hormone therapy, ccMHT continuous combined MHT, sMHT sequential MHT.

Fig. 2

Boxplots of endometrial thickness by estradiol dose. a Boxplot of endometrial thickness (ET) according to estradiol dose category (pump equivalent, PE). 1-4 PE are regulator-approved (licenced) doses; ≥ 5 PE are off-label doses. b Boxplot of endometrial thickness stratified by on-label (1-4 PE) vs off-label (≥ 5 PE) estradiol dose. The boxes includes the upper and lower quartiles (50%) of the data, the horizontal line is the median and the open circle is the mean. The whiskers extend to 1.5 times the interquartile range and data points outside this range are marked as dots. Subgroup sample sizes are included above each box and whisker.

Fig. 3

Boxplots of endometrial thickness (ET) according to progesterone dose, and progesterone/ estradiol dose. a Boxplot of endometrial thickness (ET) according to progesterone dose (low vs normal vs high dose). Oral or vaginal MP at 100 mg daily (ccMHT) or 200 mg for 12–14 days per month (sMHT) was categorised as ‘normal’ dose. MP < 100 mg daily (ccMHT) or < 200 mg for ≤ 12–14 days per month (sMHT) was classified as low MP dose; > 100 mg/day (ccMHT) or > 200 mg for ≥ 12–14 days per month (sMHT) was categorised as high dose. b Boxplot of endometrial thickness stratified by progesterone dose (low vs normal vs high dose) and estradiol dose (on- vs off-label). The on-label estradiol dose range was 1-4PE; ≥ 5PE were off-label doses. The boxes includes the upper and lower quartiles (50%) of the data, the horizontal line is the median and the open circle is the mean. The whiskers extend to 1.5 times the interquartile range and data points outside this range are marked as dots. Subgroup sample sizes are included above each box and whisker.

Fig. 4

Scatter plot of endometrial thickness (mm) according to serum estradiol concentration (pmol/L). 92 of 235 women (39.57%) had measurement of serum estradiol concentration within 3 months of the bleeding episode; 54 women (58.70%) were using an on-label dose (1-4 PE) and 38 women (41.30%) were using an off-label dose (≥ 5 PE).