Endometrial progesterone and estrogen receptors and bleeding disturbances in depot medroxyprogesterone acetate users

Akça

The European Journal of Contraception & Reproductive Health

et al. 2009

Section: Discussionmentioning

confidence: 99%

Comparison of the effects of the levonorgestrel-releasing intrauterine system (Mirena®) and depot-medroxyprogesterone acetate (Depo-Provera®) on subendometrial microvascularisation and uterine artery blood flow

Akça

The European Journal of Contraception & Reproductive Health

et al. 2009

“…ER however, is expressed at lower levels in the stroma and glands in Norplant users when compared with normal proliferative phase endometrium (Critchley et al 1993). Neither PR nor ER is altered in women using depot MPA experiencing frequent bleeding episodes when compared with women who experienced amenorrhea (Sereepapong et al 2004). However, in women using LNG-IUS, PR is suppressed (Critchley et al 1998a).…”

Section: Discussionmentioning

confidence: 99%

“…However, when exposed to lower uterine concentrations of progestogens, such as Implanon or Norplant, PR is high (Critchley et al 1993, Macpherson et al 1999. ER does not appear to be altered in Implanon users nor women using depot medroxyprogesterone acetate (MPA; Sereepapong et al 2004), however, it is lower in endometrium from Norplant users when compared with normal proliferative phase endometrium (Critchley et al 1993). Progestogens induce changes in ER and PR expression, which are likely to be involved in the observed histological differences and bleeding problems associated with specific p-only contraceptives.…”

Section: Introductionmentioning

confidence: 99%

The long-term actions of etonogestrel and levonorgestrel on decidualized and non-decidualized endometrium in a mouse model mimic some effects of progestogen-only contraceptives in women

Morison¹,

Zhang²,

Kaitu’u-Lino³

et al. 2007

Reproduction

Breakthrough bleeding (BTB), a major side effect of long-acting progestogen (p)-only contraceptives in women, is the main reason for discontinuation of their use. To understand the mechanisms of BTB, a mouse model of endometrial breakdown and repair was adapted to evaluate the effects of long-term progestogens on the endometrium. Appropriately prepared mice received either an etonogestrel (ENG)-or levonorgestrel (LNG)-releasing subdermal implant. Forty eight hours after decidualization was induced in one uterine horn the majority of tissues were highly decidualized, designated 0 day (0d). Uteri were collected subsequently at 5-day intervals (to 45d) and both decidualized and non-decidualized horns were analysed for morphological changes, leukocyte infiltration and matrix metalloproteinase expression (MMP). In decidualized horns, large blood vessels (BV) developed and disturbance of tissue integrity was observed at 5d with substantial stromal breakdown by 10d, progressing until 25d when re-epithelialization was initiated. By 45d, the tissue was restored to its pre-decidualized state but with considerable tortuosity of the luminal epithelium. Tissue remodelling was not apparent in the non-decidualized horns before 35d, when hyperproliferation of the luminal epithelium resulted in tortuosity. Changes in morphology were similar with the two progestogens, but occurred more rapidly with LNG. Apart from macrophages, few leukocytes were present in non-decidualized horns but large infiltrates of neutrophils and uterine natural killer cells (uNK) were associated with tissue breakdown in decidualized tissue, many of these cells were MMP9-positive. MMP7 was primarily associated with tissue repair. Therefore, this model mimics some of the changes observed in endometria of women using p-only contraceptives and provides an opportunity for functional studies.

Biology of Reproduction

“…Whether this is a primary or secondary event is unknown, but this information may be an important finding in attempting to characterize both the molecular etiology of implantation and the molecular pathophysiology of spontaneous abortion. Alterations in the ratio of PGR isoform expression likely cause disordered regulation of target genes, resulting in altered progestin action in the uterus [51]. Progesterone inhibits human endometrial cancer cell growth and invasiveness [52].…”

Section: Discussionmentioning

confidence: 99%

Difference in Progesterone-Receptor Isoforms Ratio Between Early and Late First-Trimester Human Trophoblast Is Associated with Differential Cell Invasion and Matrix Metalloproteinase 2 Expression

Goldman

Shalev

2006

The expression profile of the progesterone-receptor isoforms and progesterone regulation of matrix metalloproteinase 2 (MMP2) were investigated in early and late first-trimester trophoblast cells. Human trophoblast cells were obtained from legal abortions (6-12 wk of gestation). Purity of 95-98% was verified using immunohistochemistry with specific antibodies. Evaluation of cell count was performed with XTT Reagent kit, and invasion was tested using Matrigel invasion assay. Zymography was used to detect proteolytic activity, and Western blot immunoassay was used to study protein concentration. Gene expression of PGRB, PGR, and MMP2 was studied using reverse transcription-polymerase chain reaction with the housekeeping gene GAPDH used for normalization. Promoter activity was determined using luciferase reporter assay. Differential progesterone-receptor profile was documented with the dominance of PGRB in early trophoblast and the dominance of PGRA in late trophoblast. This differential profile is compatible with the inverse effect of progesterone on the two cell populations, decreasing invasion and gelatinase expression in the early first-trimester trophoblast and increasing invasion and gelatinase expression in the late first-trimester trophoblast. A decrease in MMP2 promoter activity in early trophoblast cells exposed to progesterone suggests that MMP2 expression is regulated by progesterone at the transcriptional level as well. Early trophoblast cells transfected with expressing vector for PGR encoding PGRA revealed less MMP2 activity and reversal of its response to progesterone similar to the effect observed in late trophoblast cells.