Endometrial status in post-menopausal women on long-term continuous combined hormone replacement therapy (Kliofem®) a comparative study of endometrial biopsy, outpatient hysteroscopy and transvaginal ultrasound

doi:10.1016/S0301-2115(96)02670-X

European Journal of Obstetrics & Gynecology and Reproductive Biology

Volume 72, Issue 2, April 1997, Pages 175-180

https://doi.org/10.1016/S0301-2115(96)02670-X Get rights and content

Abstract

Forty post-menopause women using a preparation of 2 mg 17 β-oestradiol and 1 mg norethisterone acetate (Kliofem®) for a mean duration of 2.9 years were investigated in an open, prospective, method comparison study. Main outcome measures were the histology of endometrial biopsy in comparison with clinical evaluation of the endometrium during panoramic hysteroscopy and endometrial thickness measured by transvaginal ultrasound. Thirty-six women had either an inactive/atrophic or unassessable endometrial biopsy, the remaining four (10%) showed benign endometrial changes. In the majority of patients the endometrium had a thin and regular appearance on hysteroscopy (92.5% of cases) with an endometrial thickness not exceeding 7 mm (90% of cases). Non-agreement between histology and hysteroscopy or transvaginal ultrasound findings was associated with the presence of polyps and submucosal fibroids, or innocuous endometrial changes such as a pseudodecidual pattern. No case of malignancy was encountered in any patient in this study. The present study suggests that continuous combined hormone replacement therapy appears to be safe with regard to endometrial health. In the majority of women an inactive endometrium or non-assessable biopsy result will be encountered. However, the numbers examined here are small and endometrial carcinoma has been reported to occur. Continuing follow-up of patients on continuous combined HRT is therefore essential.

References (28)

MH Thom et al.
Prevention and treatment of endometrial disease in climacteric women receiving oestrogen therapy
Lancet
(1979)
IS Fraser
A review of the role of progestogens in hormone replacement therapy: Influence on bleeding patterns
Maturitas
(1986)
SG Prough et al.
Continuous estrogen progestin therapy in the menopause
Am J Obstet Gynecol
(1987)
L Weinstein et al.
Evaluation of a continuous combined low-dose regimen of estrogen-progestin for treatment of the menopausal patient
Am J Obstet Gynecol
(1990)
EB Obel et al.
A two-year double-blind controlled study of the clinical effect of combined and sequential postmenopausal replacement therapy and steroid metabolism during treatment
Maturitas
(1993)
TC Hillard et al.
Continuous combined conjugated equine estrogen-progestogen therapy: Effects of medroxyprogesterone acetate and norethindrone acetate on bleeding patterns and endometrial histologic diagnosis
Am J Obstet Gynecol
(1992)
SR Goldstein et al.
Endometrial assessment by vaginal ultrasonography before endometrial sampling in patients with postmenopausal bleeding
Am J Obstet Gynecol
(1990)
AC Fleischer et al.
Sonographic depiction of the endometrium during normal cycles
Ultrasound Med Biol
(1986)
R Osmers et al.
Vaginography for early detection of endometrial carcinoma?
Lancet
(1990)
AL Magos et al.
The effects of norethisterone in postmenopausal women on oestrogen replacement therapy, a model for premenstrual tension syndrome
Br J Obstet Gynaecol
(1986)

AL Magos et al.

Amenorrhoea and endometrial atrophy with continuous oral oestrogen and progestogen therapy in postrnenopausal women

Obstet Gynecol

(1985)

T Sporrong et al.

Comparison of four continuously administered progesterone plus oestradiol combinations for climacteric complaints

Br J Obstet Gynaecol

(1988)

B Staland

Continuous treatment with a combination of estrogen and gestagen, a way of avoiding endometrial stimulation

Clinical experiences with Kliogest

Acta Obstet Gynaecol Scand

(1985)

L Weinstein

Efficacy of a continuous estrogen-progestin regimen in the menopausal patient

Obstet Gynecol

(1987)

Cited by (29)

Physiologic and exogenous hormone effects on the endometrium: important aspects for the surgical pathologist
2017, Diagnostic Histopathology
Citation Excerpt :
In fact, studies have shown a protective effect with the use of combined continuous regimens38 as well as normalization of atypical hyperplasia.39 Benign endometrial polyps may be present in women on HRT, and occur more commonly in patients on cyclic regimens as compared to combined continuous therapy.40 Progestins represent different types of synthetic progesterone.
The endometrium exhibits a unique physiology in its ability to cyclically respond to steroid hormones, resulting in morphologic changes that allow the pathologist's interpretation of proper endometrial function. Distinctive changes are also observed during times of physiologic hormonal changes, such as in pregnancy, or in pathologic and iatrogenic hormonal imbalances, as in certain functioning ovarian tumours and hormone therapy, respectively. The ubiquity of these states, in particular the widespread use of oral contraception, hormone replacement therapy, hormonal intrauterine devices, and nowadays frequent use of progestin as treatment for endometrial hyperplasia and carcinoma, requires that the pathologist be familiar with both the patient history as well as the histologic patterns specific to each entity in order to render an accurate, practical diagnosis for the clinician. Notably, some changes may mimic more worrisome lesions, and vigilance of these similarities and differential diagnosis is necessary in the evaluation of endometrial samples.
An update regarding the effects of hormones on the endometrium: Practical considerations for the surgical pathologist
2013, Diagnostic Histopathology
Citation Excerpt :
The benefit of this mode of therapy is the absence of hyperplasia or carcinoma: in fact, studies have shown a protective effect when combined continuous regimens are used,38 as well as frequent normalization of endometrial complex hyperplasia.39 Benign endometrial polyps may be present in women on HRT and tend to occur more commonly in patients on cyclic regimens in comparison with those on a combined continuous therapy regimen.40 Progestins are drugs that represent different formulations of progesterone.
The endometrium displays a unique physiology characterized by its cyclical response to steroid hormones, which results in morphological changes that contribute to a pathologist's interpretation of proper endometrial function. Distinctive changes are also observed during times of physiological hormonal shifts (such as during pregnancy), pathological hormonal imbalances (such as certain functioning ovarian tumours) and iatrogenic hormonal imbalances (such as hormone therapy). The ubiquity of these states, particularly in conjunction with the widespread use of oral contraceptives, hormone replacement therapy, and intrauterine devices, requires that the pathologist be familiar with both the complete patient history and the histologic patterns specific to each entity in order to obtain an accurate and practical diagnosis for the clinician. Furthermore, some endometrial changes may mimic more worrisome lesions, and vigilance is necessary to accurately distinguish among these histologic patterns when evaluating endometrial samples.
Hyperplasias of the Endometrium
2004, Gynecologic Cancer: Controversies in Management
Comparative endometrial histology in postmenopausal women with sequential hormone replacement therapy of estradiol and, either chlormadinone acetate or micronized progesterone
2002, Maturitas
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.
Endometrial safety of hormone replacement therapy: Review of literature
2002, Maturitas
Unopposed estrogens for treating menopausal symptoms were extensively used when epidemiological findings associated them with an increased endometrial cancer risk. Adding progestogens reverse this side effect efficiently but patient, dose, type and especially time during which the progestogen is administered are important. Long-term uterine safety of the long cycle HRT with administration of the progestogen every 3 months remains unclear. Because regular bleeding lowers compliance, continuous combined estrogen–progestogen treatment has become popular. Many different regimens are now available using oral, transdermal, subcutaneous, intravaginal or intra-uterine application of the estrogen and/or progestogen. Available but inadequate studies seem to point towards a slightly decreased endometrial cancer risk with continuous combined preparations compared with non-HRT-users and an increased risk with long-term oral but not vaginal treatment with low-potency estrogen formulations such as estriol. Newer compounds for menopausal health such as tibolone and raloxifene seem to be safe. As for any women with abnormal vaginal bleeding, those on HRT must have an intra-uterine evaluation. Transvaginal ultrasound (TVU) is very accurate in predicting a normal uterine cavity but inaccurate in predicting endometrial pathology because of a low specificity and positive predictive value of a thick echogenic endometrium. In all such cases a three-dimensional visualisation of intra-uterine lesions is more accurate. Periodic examination with TVU and/or endometrial biopsy of HRT exposed endometrium in asymptomatic women is not cost-effective. The available limited data on the use of HRT in hysterectomised women for early stage endometrial cancer show little evidence in terms of recurrence.
Influence of estradiol and gestagens on oxidative stress in the rat uterus
2002, Gynecologic Oncology
Objective. We studied the effect of ovariectomy, estradiol (E2), and E2 + medroxyprogesterone (MPA) on the Wistar rat uterus.
Methods. We used 15 adult female rats. The study was divided into the following four stages: (a) extirpation of the upper half of the left hemi-uterus (basal state) and ovariectomy; (b) animals were maintained for 15 days without treatment, performance of a new laparotomy, and extirpation of the remaining left hemi-uterus (OVX state); (c) beginning of E2 replacement therapy (ERT) (8 μg/day) for 15 days, followed by extirpation of the upper half of the right hemi-uterus (ERT state); and (d) the administration of E2 was continued, and oral treatment with MPA was begun (20 μg/day) to last for a further 15 days. At the end of the combined hormone replacement therapy (HRT) the remaining right hemi-uterus was extirpated (HRT state). At the end of each intervention, the plasma concentrations of E2 and PRG were measured.
Results and Discussion. The ovariectomy significantly reduced the malonaldehyde (MDA) levels (P < 0.0008) and catalase activity (P < 0.0006). The ERT very significantly (P < 0.0033) raised the catalase and MDA levels; these significance levels were maintained after the Bonferroni method was applied (overall error 5%). The HRT reduced the levels of MDA and catalase, but not significantly after the Bonferroni test was applied.
Conclusions. Uterine oxidative stress is increased by E2, resulting in a significant increase in MDA. This may be modulated in part by the catalase activity. Although it cannot be confirmed categorically, MPA seems to intervene by decreasing the said oxidative stress.

View all citing articles on Scopus

View full text

Endometrial status in post-menopausal women on long-term continuous combined hormone replacement therapy (Kliofem®) a comparative study of endometrial biopsy, outpatient hysteroscopy and transvaginal ultrasound

Abstract

Lancet

Maturitas

Am J Obstet Gynecol

Am J Obstet Gynecol

Maturitas

Am J Obstet Gynecol

Am J Obstet Gynecol

Ultrasound Med Biol

Lancet

The effects of norethisterone in postmenopausal women on oestrogen replacement therapy, a model for premenstrual tension syndrome

Br J Obstet Gynaecol

Amenorrhoea and endometrial atrophy with continuous oral oestrogen and progestogen therapy in postrnenopausal women

Obstet Gynecol

Comparison of four continuously administered progesterone plus oestradiol combinations for climacteric complaints

Br J Obstet Gynaecol

Continuous treatment with a combination of estrogen and gestagen, a way of avoiding endometrial stimulation

Clinical experiences with Kliogest

Acta Obstet Gynaecol Scand

Efficacy of a continuous estrogen-progestin regimen in the menopausal patient

Obstet Gynecol

Endometrial status in post-menopausal women on long-term continuous combined hormone replacement therapy (Kliofem^®) a comparative study of endometrial biopsy, outpatient hysteroscopy and transvaginal ultrasound