Effect of Oral versus Vaginal Administration of Estradiol and Dydrogesterone on the Proliferative and Secretory Transformation of Endometrium in Patients with Premature Ovarian Failure and Preparing for Assisted Reproductive Technology

Abstract

Purpose: This study aimed to assess the efficacy of vaginally versus orally administered estradiol (E₂) and dydrogesterone (DG) on the proliferative and secretory transformation of endometrium in patients with premature ovarian failure (POF) and preparing for assisted reproductive technology.

Methods: Twenty patients with POF who were awaiting oocyte donation were included in the study; they were randomly assigned to two groups to receive E₂ and DG either orally or vaginally. Treatment efficacy was compared between the two groups regarding blood E₂ concentrations, endometrial thickness, histology using hematoxylin and eosin staining, immunohistochemical analysis of ER expression, and PR and pinopodes morphology using scanning electron microscopy.

Results: E₂ concentrations differed significantly between oral and vaginal E₂ and DG administration for 14 days (82.3 vs 1015.6 pg/mL; P < 0.001) and 21 days (85.0 vs 809.8 pg/mL; P < 0.001). Endometrial thickening was more pronounced in the vaginal treatment group, and also ER staining was stronger on days 14 and 21 in the vaginal treatment group. PR staining in the endometrium appeared more intense in the oral treatment group, which was, however, not significant. The abundance of developing pinopodes was higher in the vaginal treatment group (P = 0.04).

Conclusion: Vaginal administration of E₂ and DG is more effective than oral administration regarding proliferative and secretory transformation of the endometrium in POF patients and preparing for assisted reproductive technology.

Keywords: micronized estradiol; oral administration; pinopodes; premature ovarian failure; vaginal administration.

Figure 1

Proliferative and secretory transformation of endometrium via the vaginal and oral route of estradiol and dydrogesterone (DG). Photomicrographs (×200) showing the amounts of glands in the vaginal group (C, D) were more than the oral (A, B). After 14 days of therapy, the vaginal group had pseudostratified columnar epithelium, curved glands, intercellular substance edema and spindle-shaped cells (C). On day 21 the vaginal group had bigger, curved, serrate glands, active apocrine secretion, large and round interstitial cells, apparent edema and glandular lumens existed secretions. After 21 days of therapy, the vaginal group had bigger, curved, serrate glands, active apocrine secretion, large and round interstitial cells, apparent edema and glandular lumens existed secretions.

Figure 2

Photomicrographs (×200) showing immunohistochemical localization of ER in endometrium from oral and vaginal women. Both glandular epithelial and stromal compartments demonstrated more intense nuclear immunoreactivity for ER on day 14 (the proliferative phase) (a, c, (A)) than on day 21 (the secretory phase) (b, d, (A)) and more intense in the vaginal versus oral group (*P<0.05, (B)). GE= glandular epithelium. P values are for Mann–Whitney U-test. HSCORE:∑pi(i+1), where i = the intensity of staining, with a value of 1, 2, or 3 (weak, positive, or strong, respectively), and pi = the proportion of stained epithelial cells, varying from 0 to 100%.

Figure 3

Photomicrographs (×200) showing immunohistochemical localization of PR in endometrium from oral and vaginal women. Both glandular epithelial and stromal compartments demonstrated more intense nuclear immunoreactivity for PR on day 14 (a, c, (A)) than on day 21 (b, d, (A)) and more intense in the oral (a, b, (A)) versus vaginal group (c, d, (A)), but there were no significant differences(*P>0.05, (B)). P values are for Mann–Whitney U-test.

Figure 4

(A) Scanning electron micrograph showing the apical surface of the luminal uterine epithelium in endometrial samples obtained on day 21. Note the absence of pinopodes (a) and the presence of the developing pinopodes (b, c, d). Scale bars = 10μm. (B) Only 3 of the oral group patients showed developing pinopodes on day 21, while 8 patients in the vaginal group were observed (P=0.04). None of them showed fully developed pinopodes. P values are for Chi‑square test.