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Angiogenesis in the endometrium of leiomyoma-related abnormal uterine bleeding.


- candidate number24418
- NTR NumberNTR5877
- ISRCTNISRCTN no longer applicable
- Date ISRCTN created
- date ISRCTN requested
- Date Registered NTR30-mei-2016
- Secondary IDsMETc VUMC / CMG nummer 2015-479 / VUMC2015-573
- Public TitleAngiogenesis in the endometrium of leiomyoma-related abnormal uterine bleeding.
- Scientific TitleThe role of angiogenesis in the endometrium in the etiology of leiomyoma-related abnormal uterine bleeding: a prospective controlled in vitro studies
- ACRONYMANGHYS study
- hypothesisThe hypothesis is that the overexpression of angiogenic factors produced by leiomyoma stimulates the angiogenesis in endometrium which induces abnormal uterine bleeding.
- Healt Condition(s) or Problem(s) studiedMyoma, Endometrium, Angiogenesis, Abnormal uterine bleeding
- Inclusion criteria Signed informed consent
> 18 years
Premenopausal
Myomectomy for bleeding disorders
Hysterectomy for bleeding disorders and fibroids
Hysterectomy for non-bleeding disorders (no fibroids)
- Exclusion criteria Uterine abnormalities (except fibroids) such as endometrial polyps and adenomyosis
deep infiltrating endometriosis,
pelvic inflammatory disease (PID),
previous occlusion or embolization of uterine vessels
malignancy of cervix, endometrium, myometrium or ovary
- mec approval receivedyes
- multicenter trialyes
- randomisedno
- groupParallel
- Type2 or more arms, non-randomized
- Studytypeobservational
- planned startdate 15-dec-2015
- planned closingdate1-nov-2017
- Target number of participants60
- InterventionsThe patient will not undergo any specific interventions related to this study other than regular treatment for fibroids or heavy menstrual bleeding. Residual fibroid and endometrial tissue will be collected for this study and processed for experiments. From the fibroid tissue and normal myometrium secretome will be prepared and the endometrium tissue will be used for immunohistostaining.
The influence on angiogenis of the secretome will be compared within an in vitro model.
- Primary outcomeHistopathologic study:
Microvascular density (MVD), by the stained CD31/CD34.

In vitro study
Time of recovery of HUVEC monolayer confluency, which gives a level of migration index.
Quantity of ATP present, equivalent to the presence of metabolically active HUVEC and consequently the degree of proliferation.
Motility index of HUVEC, which resembles the sprouting.
- Secondary outcomeHistopathologic study:
Endothelial proliferation index, as ratio of expression of double stained CD31/CD34 and Ki-67.
The expression of actin (SMA positive vessels), which resemble the mature, pericyte covered vessels.
Difference in absolute number and percentage of pericyte-naked / immature vessels.
- Timepointsnot applicable
- Trial web sitenot applicable
- statusopen: patient inclusion
- CONTACT FOR PUBLIC QUERIESdr. F.A. Groenman
- CONTACT for SCIENTIFIC QUERIESMD. PhD. J.A.F. Huirne
- Sponsor/Initiator VU University Medical Center
- Funding
(Source(s) of Monetary or Material Support)
VU University Medical Center
- Publications
- Brief summaryUterine leiomyoma (UL) are benign tumors of the smooth-muscle cells of the uterus which affect a lot of women. The most common symptom is abnormal uterine bleeding (AUB) resulting in negative effects on health related quality of life. While there are several noninvasive and invasive therapies treating symptoms, the exact etiology of the leiomyoma-related bleeding is still unknown.

Increased vasculature in the endometrium overlaying leiomyoma seen during hysteroscopy, together with larger venous dilatations in endometrium of myomatous uteri compared with normal uteri, triggered the idea that increased angiogenesis may play a role in leiomyoma-related AUB. Angiogenesis and angiogenic factors play an essential role in the regeneration of the endometrium during menstruation. However, an overexpression of these factors may lead to decreased vessel integrity and increased permeability, leading to leakiness en bleeding. The hypothesis is the overexpression of angiogenic factors produced by leiomyoma stimulates the angiogenesis in endometrium which induces abnormal uterine bleeding.
Objective of the study:
The degree of angiogenesis and the effect on the endometrium will be examined in uteri with and without leiomyoma.

Study design: Prospective controlled histoparhologic and in vitro study

Study population: Premenopausal women who underwent a hysterectomy or a hysteroscopic resection of leiomyoma. Control patients, premenopausal women who underwent hysterectomy for other reasons than uterine leiomyomas or heavy menstrual bleeding.

Intervention: Residual fibroid and endometrial tissue will be collected for this study and processed for experiments. From the fibroid tissue and normal myometrium secretome will be prepared and the endometrium tissue will be used for immunohistostaining.
The influence on angiogenis of the secretome will be compared within an in vitro model.

Histopathologic study:
Vascular density
Endothelial proliferation index
Presence of immature vessels


In vitro study
Level of proliferation
Migration capacity
Sprouting index

Primary study parameters:
Histopathologic study:
Microvascular density (MVD), by the stained CD31/CD34.

In vitro study
Time of recovery of HUVEC monolayer confluency, which gives a level of migration index.
Quantity of ATP present, equivalent to the presence of metabolically active HUVEC and consequently the degree of proliferation.
Motility index of HUVEC, which resembles the sprouting.

Secundary study parameters:
Endothelial proliferation index, as ratio of expression of double stained CD31/CD34 and Ki-67.
The expression of actin (SMA positive vessels), which resemble the mature, pericyte covered vessels.
Difference in absolute number and percentage of pericyte-naked / immature vessels.
- Main changes (audit trail)
- RECORD30-mei-2016 - 2-jul-2016


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