Elsevier

Maturitas

Volume 41, Issue 2, 26 February 2002, Pages 115-121
Maturitas

Comparative endometrial histology in postmenopausal women with sequential hormone replacement therapy of estradiol and, either chlormadinone acetate or micronized progesterone

https://doi.org/10.1016/S0378-5122(01)00260-2Get rights and content

Abstract

Objectives: To determine the endometrial response in postmenopausal women treated with a sequential hormone replacement therapy (HRT) of estradiol and, either chlormadinone acetate (CA) or micronized progesterone (MP). Methods: Three hundred and thirty-six postmenopausal women with a normal endometrium were randomized in the double-blind study. All patients received percutaneous estradiol 1.5 mg/day from day 1 to day 24 and either CA 10 mg/day or oral MP 200 mg/day from day 10 to day 24. The total duration of treatment was 18 months. Endometrial biopsies were performed before treatment and between day 18 and day 24 of the 18th month of HRT. Results: Of the 336 patients selected, 317 had a biopsy at inclusion. Of them, 244 patients (124 in the CA group and 120 in the P group) were suitable for evaluation for analysis at the 18th month. Insufficient sampling occurred in 33.9% in the CA group and 60% in the MP group (probably atrophic). No case of hyperplasia could be reported in both groups. The endometrium was atrophic in 19.5 versus 27.1%, proliferative in 3.7 versus 8.3% and secretory in 76.8 versus 62.5% in CA and MP groups, respectively. It was possible to see histological differences induced by the two progestins. The CA endometria showed fewer glands lined by a cubo-cylindrical epithelium, with an edematous stroma, compared to the MP endometria which had more glands lined by a cylindrical epithelium, stroma being poorly edematous. These figures varied in intensity due to the length of progestative impregnation, predecidualization occurring later in the CA group, with distended capillaries. Conclusions: These results show that CA 10 mg/day is a powerful progestin compared to MP 200 mg/day, on weakly estradiol-primed endometria, giving a molecule-specific histological aspect with a good endometrial safety.

Introduction

During life, the endometrium is a very sensitive target for estradiol which induces a proliferation phase and for progesterone which induces a transformation of estradiol-primed endometria in secretory phase. Steroid receptors are located in glands, stroma and vessels. After menopause, hormonal receptors are still present but the vascularization is altered. This allows different interindividual and intraindividual behavior; the same endometrium can respond differently and show diverse histological aspects allowing some difficulty for interpretation [1]. The hormonal histological status is related as proliferative or secretory with a precise dating for the luteal phase of physiological cycles. This situation can be reproduced on a menopausal endometrium, but, in most hormone replacement therapies (HRTs), estradiol stimulation is generally weak and, in contrast, progestin action strong, to prevent hyperplasia and carcinoma.

The different progestins have some specific impact on the different structures of the endometrium. Among these, chlormadinone acetate (CA)—a non-androgenic pregnane progestin—has been used, with success, for luteal insufficiency during the last 25 years. The present study has been developed to compare the histological effects of CA and MP on endometrium, in sequential HRT in menopausal women.

Section snippets

Patients

A multicentric, double-blind, randomized trial was conducted for 18 months in healthy postmenopausal patients selected in the out-patient department. A first endometrial biopsy was performed at inclusion, and another one was done at the end of the trial 18 months later; this last biopsy was performed between day 18 and day 24 of the cycle, in the progestative phase.

Administration regimen

After randomization, patients received during the 18 months percutaneous E2 (Oestrogel®) 1.5 mg/day from day 1 to day 24 of the

Results

The study took place in France between November 1991 and December 1994. A total of 336 postmenopausal women were included: 167 were randomized to receive E2/CA (CA group), and 169 to receive E2/P (P group). The mean age was 51.3±3.8 years in the two groups and duration of menopause was 14.1±15.9 months in CA group and 17.9±22.3 months in MP group. Mean plasmatic basal levels were, for CA and MP groups, respectively, 68.0±63.6 and 66.1±44.1 pmol/l for estradiol, and 88.1±41.2 and 78.0±34.0 IU/l

Discussion

Most tissues are now usually fixed by a neutral formaldehyde, which represents an universal fixative suitable for routine histological analysis as well as new techniques such as in situ hybridization. But, when the tissues are not supported by a fibrosis stroma, formaldehyde appears as a poor morphologic fixative. This is the case for testicular biopsies, which are nearly not interpretable for the study of spermatogenesis and for endometrial biopsies to a lesser extent. We choose the Bouin

Acknowledgements

This work was supported by Aventis Laboratories, France.

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