Abstract
Objectives: Endometrial homeostasis, indicated as the balance between apoptosis and proliferation,
was studied with regard to endometrial safety and bleeding disturbances. Materials and methods: The quantitatively sufficient endometrial biopsies of 92 postmenopausal women enrolled
in the study were investigated. The participants were divided into two groups, each
receiving a continuous combined HRT regimen with either conjugated estrogen (CE) ![Math Eq]()
mg medroxyprogesterone acetate (MPA) (=CE/MPA) or 17-β-estradiol (E2) ![Math Eq]()
mg norethisterone acetate (NETA) (=E2/NETA). These were evaluated according to apoptotic
index (Ai) and proliferation marker Ki-67 index. Estrogen receptor α (ER) and progesterone
receptor (PR) expression were also monitored, as well as endometrial thickness. Quantitative
in situ techniques were used. Results: Ai and Ki-67 index were unchanged in epithelial glands of endometrium from baseline
to second biopsy obtained after 1 year of combined continuous HRT. In stromal tissue,
Ki-67 index was increased, while Ai was on the same level. PR expression in both epithelium
and stroma was unchanged. Endometrial thickness was unaffected during therapy, and
the histopathological evaluation showed no development of hyperplasia or carcinoma.
Conclusions: The unaffected homeostasis in endometrial epithelium contributes to endometrial safety
and is in accordance with the histopathological findings of no hyperplasia. The homeostasis
of stroma was transformed to be more proliferative. Increased stromal proliferation
may be of importance for stromal support of the veins and for decreasing breakthrough
bleeding during HRT. The increased stromal proliferation, as well as the decreased
ER expression both in epithelium and stroma, could be an effect of progesterone.
mg medroxyprogesterone acetate (MPA) (=CE/MPA) or 17-β-estradiol (E2) 
mg norethisterone acetate (NETA) (=E2/NETA). These were evaluated according to apoptotic
index (Ai) and proliferation marker Ki-67 index. Estrogen receptor α (ER) and progesterone
receptor (PR) expression were also monitored, as well as endometrial thickness. Quantitative
in situ techniques were used. Results: Ai and Ki-67 index were unchanged in epithelial glands of endometrium from baseline
to second biopsy obtained after 1 year of combined continuous HRT. In stromal tissue,
Ki-67 index was increased, while Ai was on the same level. PR expression in both epithelium
and stroma was unchanged. Endometrial thickness was unaffected during therapy, and
the histopathological evaluation showed no development of hyperplasia or carcinoma.
Conclusions: The unaffected homeostasis in endometrial epithelium contributes to endometrial safety
and is in accordance with the histopathological findings of no hyperplasia. The homeostasis
of stroma was transformed to be more proliferative. Increased stromal proliferation
may be of importance for stromal support of the veins and for decreasing breakthrough
bleeding during HRT. The increased stromal proliferation, as well as the decreased
ER expression both in epithelium and stroma, could be an effect of progesterone.Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to MaturitasAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Endometrial carcinoma: two diseases?.Cancer Detect. Prev. 1987; 10: 237-246
- Estrogen replacement therapy induces telomerase RNA expression in the macaque endometrium.Fertil. Steril. 2002; 77: 601-608
- Molecular events in endometrial carcinogenesis.Int. J. Gynecol. Cancer. 1996; 6: 425-438
- Human 17 beta-hydroxysteroid dehydrogenase type 1 and type 2 isoenzymes have opposite activities in cultured cells and characteristic cell- and tissue-specific expression.Biochem. J. 1996; 314: 839-845
- Progestin regulation of cellular proliferation.Endocrinol. Rev. 1990; 11: 266-272
- Endometrial microstructure: structure-function relationship throughout the menstrual cycle.Semin. Reprod. Endocrinol. 1983; 1: 205-219
- Regulation of estrogen/progestogen receptors in the endometrium.Int. J. Fertil. 1996; 41: 16-21
- Menopause and hormone replacement therapy: an overview.Obstet. Gynecol. 1996; 87: 2S-15S
- Bleeding patterns in postmenopausal women using continuous combination hormone replacement therapy with conjugated estrogen and medroxyprogesterone acetate or with l7 beta-estradiol and norethindrone acetate.Am. J. Obstet. Gynecol. 2001; 184: 131-138
- Histologic classification and pathologic findings for endometrial biopsy specimens obtained from 2964 perimenopausal and postmenopausal women undergoing screening for continuous hormones as replacement therapy (CHART 2 Study).Am. J. Obstet. Gynecol. 1997; 176: 377-380
- Transvaginal ultrasonography of the endometrium in women with postmenopausal bleeding—a Nordic multicenter study [see comments].Am. J. Obstet. Gynecol. 1995; 172: 1488-1494
- Superficial endometrial vascular fragility in Norplant users and in women with ovulatory dysfunctional uterine bleeding.Hum. Reprod. 2000; 15: 1509-1514
- Apoptosis: the biochemistry and molecular biology of programmed cell death.Endocrinol. Rev. 1993; 14: 133-151
- Active cell death in hormone dependent tissue.Cancer Metastasis Rev. 1992; 11: 197-220
- Regulation of apoptosis by steroid hormones.J. Steroid Biochem. Mol. Biol. 1995; 53: 1-8
- Characterization of uterine epithelium apoptotic cell death kinetics and regulation by progesterone and RU 486.Am. J. Anat. 1992; 140: 449-456
- Atrophy and apoptosis in the cyclical human endometrium.J. Pathol. 1975; 119: 159-166
- The patterns of expression of an apoptosis-related CK18 neoepitope, the bcl-2 proto-oncogene, and the Ki-67 proliferation marker in normal, hyperplastic, and malignant endometrium.Int. J. Gynecol. Pathol. 2000; 19: 118-126
- Apoptosis, bcl-2 expression, and proliferation in benign and malignant endometrial epithelium: an approach using multiparameter flow cytometry.Gynecol. Oncol. 2000; 77: 11-17
- bcl-2 is down-regulated in atypical endometrial hyperplasia and adenocarcinoma.Mod. Pathol. 1996; 9: 430-438
- Apoptosis and the expression of Bax and Bc 1–2 in hyperplasia and adenocarcinoma of the uterine endometrium.Hum. Reprod. 2001; 16: 2211-2218
- Transdermal sequential and continuous hormone replacement regimens with estradiol and norethisterone acetate in postmenopausal women: effects on the endometrium.Int. J. Fertil. Womens Med. 1997; 42: 388-398
- Low dose transdermal estradiol/norethisterone acetate treatment over 2 years does not cause endometrial proliferation in postmenopausal women.Menopause. 2002; 9: 137-144
- Ki-67 immunostaining of endometrial biopsies with special reference to hormone replacement therapy.Gynecol. Obstet. Invest. 1995; 39: 120-124
- Continuous transdermal oestrogen and interrupted progestogen as a novel bleed-free regimen of hormone replacement therapy for postmenopausal women.Br. J. Obstet. Gynaecol. 1997; 104: 1184-1190
- Production of the mouse monoclonal antibody reactive with a human nuclear antigen associated with cell proliferation.Int. J. Cancer. 1983; 31: 13-20
- Micronized progesterone regulation of the endometrial glandular cycling pool.Int. J. Gynecol. Pathol. 2001; 20: 374-379
- Apoptosis occurs more frequently in intraductal carcinoma than in infiltrating duct carcinoma of human breast cancer and correlates with altered p53 expression: detected by terminal-deoxynucleotidyl-transferase-mediated dUTP-FITC nick end labelling (TUNEL).Histopathology. 1997; 31: 534-539
- Apoptosis: a basic biological phenomenon with wideranging implications in tissue kinetics.Br. J. Cancer. 1972; 26: 239-259
- Apoptosis, proliferation, and sex hormone receptors in superficial parts of human endometrium at the end of the secretory phase.J. Am. Endocrinol. Metab. 1999; 84: 1737-1743
- Expression of messenger ribonucleic acid encoding matrix metalloproteinases and their tissue inhibitors is related to menstruation.J. Endocrinol. 1994; 141: R1-R3
- Leukocyte networks and human endometrial remodelling.J. Reprod. Immunol. 2002; 57: 95-108
- Effects of various types and dosages of progestogens on the postmenopausal endometrium.J. Reprod. Med. 1982; 27: 538-548
Ferenzy A. Regeneration of the human endometrium. New York: Masson Publications; 1980.
- Endometrial thickness and oestradiol concentration in women with bleeding complaints during use of Norplant implants.Hum. Reprod. 1998; 13: 188-191
- Transvaginal sonography of the endometrium in a representative sample of postmenopausal women.Ultrasound Obstet. Gynecol. 1996; 7: 322-327
- The effects of oral estriol on the endometrium in postmenopausal women.Maturitas. 2002; 42: 149-156
- Immunohistochemical analysis of distribution of estrogen receptors and progesterone receptors in the postmenopausal endometrium.Acta Obstet. Gynecol. Scand. 1996; 75: 702-706
- The effects of tamoxifen on proliferation and steroid receptor expression in postmenopausal endometrium.J. Clin. Pathol. 2002; 55: 514-519
- Progesterone therapy for endometrial carcinoma reduces cell proliferation but does not alter apoptosis.Cancer. 1997; 83: 111-121
- Hormonal pathology of the endometrium.Mod. Pathol. 2000; 13: 285-294
- Apoptosis and apoptosis-associated parameters in relation to tamoxifen exposure in postmenopausal endometrium.Hum. Pathol. 2002; 33: 341-346
Article info
Publication history
Accepted:
December 1,
2003
Received in revised form:
November 9,
2003
Received:
July 23,
2003
Identification
Copyright
© 2004 Elsevier Ireland Ltd. Published by Elsevier Inc. All rights reserved.
