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Norwegian Adenomyosis Study II: Gene Expression Profiling of Adenomyosis (NAPPED II)

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ClinicalTrials.gov Identifier: NCT02197923
Recruitment Status : Active, not recruiting
First Posted : July 23, 2014
Last Update Posted : August 20, 2019
Sponsor:
Collaborators:
University of Oslo
Helse Sor-Ost
Information provided by (Responsible Party):
Tina Tellum, Oslo University Hospital

Brief Summary:

Adenomyosis is characterized by the appearance of endometrial cells in the muscular layer of the uterus. It affects about 15-20% of the female population.

The symptoms of adenomyosis are heavy menstrual bleedings and painful menstruation (dysmenorrhea) and in addition chronic pelvic pain. Subfertility and infertility have been correlated with adenomyosis.

Parity, age and uterine abrasion increase the risk of adenomyosis. Hormonal factors such as local hyperestrogenism and elevated levels of prolactin (PRL) have been identified, but autoimmune and mechanical factors are also hypothesized.

Regarding treatment, the most effective measure is hysterectomy. As this is a very drastic measure in younger women, levonogestrel-releasing intrauterine devices, Gonadotropin releasing hormone (GnRH)-analogues, Danazol, uterine embolization and endometrial ablation have been tried, but studies are few in number, retrospective, and have small sample sizes.

Adenomyosis has so far not been subject to extensive research efforts. The pathogenesis of adenomyosis remains still unclear, there are not many satisfying treatment options and diagnostics include mostly magnetic resonance imaging (MRI) and histology.

The investigators designed a series of 3 studies with a broad approach in understanding adenomyosis. This is part 2.

In this study the investigators take both tissue samples and blood samples that will be investigated in order to understand the basic processes leading to adenomyosis.


Condition or disease Intervention/treatment
Adenomyosis Procedure: Myometrial biopsy Procedure: endometrial biopsy

Detailed Description:

Biopsy of focal adenomyosis of the myometrium:

This will be an extension of the NAPPED1-study. The investigators will perform ultrasound-guided transvaginal biopsies of the myometrium and collect venous blood samples.

As recent studies have suggested abnormalities in the regulation of specific genes in the development of adenomyosis, the investigators want to investigate differentially expressed genes in adenomyosis compared to eutopic endometrium. Using microarrays, the investigators can simultaneously screen differences in expression of thousands of genes in samples from the two groups. Profiling studies performed on endometrium of healthy individuals and of endometriosis show results that enable identification of biological processes and molecular mechanisms. Expression profiles can be used to identify molecular targets for therapeutic purposes. There are some very interesting studies that investigate drug treatment on a molecular level e.g. the effect of Danazol treatment on eutopic and ectopic endometrial tissue, but intramural adenomyosis has not been subject to gene profiling yet.

Tissue samples can be easily obtained after hysterectomy, but those samples will only represent older women, and cannot be used for consecutive monitoring of biochemical effects of treatment, as the uterus is removed. In order to investigate the pathophysiology of adenomyosis in younger women, and compare it to those in older individuals, as well as to evaluate effects of treatment, it is necessary to be able to obtain in-vivo samples.

The plan is therefore to take transvaginal, ultrasound-guided biopsy-samples from the uterus (myometrium) of all included patients at the beginning of their surgery, when the patient is under full anesthesia. The safety of comparable procedures has been shown in prior studies, but the investigators will further validate the safety of this method. The investigators believe that an in-vivo biopsy is a safe measure, and that representative samples of adenomyosis can be obtained.

The challenge with adenomyosis is that it is located intramyometrially. A transcervical biopsy will contaminate the sample with eutopic endometria, therefore it is most meaningful to take the biopsy transvaginally, but not through the cavity. After obtaining the biopsy sample, it will be examined histologically by imprint, to confirm if glandular cells are contained where expected. When good routines show a reliable level of specificity, the investigators will go further by selecting approximately 10 patients for gene profiling of adenomyosis. The investigators will also use endometrial biopsies (Pipelle) from those patients to see if there is a difference between intramural adenomyosis and their eutopic endometria. Most patients that undergo hysterectomy have taken a pipelle-biopsy routinely.

The levels of prolactin, Anti-müllerian hormone (AMH), Follicle stimulating hormone (FSH), luteinizing hormone (LH) and estrogen will also be taken, in order to determine if the severity of adenomyosis is only related to age as shown before, or also to hormonal activity.


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Study Type : Observational
Estimated Enrollment : 80 participants
Observational Model: Case-Control
Time Perspective: Prospective
Official Title: Norwegian Adenomyosis Study: Pathophysiology, Peristalsis, Expression Profiling and Diagnosis, Part 2
Actual Study Start Date : August 6, 2014
Estimated Primary Completion Date : November 1, 2019
Estimated Study Completion Date : December 1, 2019

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Biopsy

Group/Cohort Intervention/treatment
Biopsy: adenomyosis
Myometrial biopsy Pipelle
Procedure: Myometrial biopsy
transvaginal ultrasound guided biopsy of the myometria

Procedure: endometrial biopsy
transcervical endometrial biopsy
Other Name: Pipelle

Biopsy: Healthy
Myometrial Biopsy Pipelle
Procedure: Myometrial biopsy
transvaginal ultrasound guided biopsy of the myometria

Procedure: endometrial biopsy
transcervical endometrial biopsy
Other Name: Pipelle




Primary Outcome Measures :
  1. Sensitivity and specificity of biopsies for adenomyotic tissue in percent (%) [ Time Frame: At time of hysterectomy ]
    Sensitivity and specificity of ultrasound guided myometrial biopsies for adenomyotic tissue


Secondary Outcome Measures :
  1. multiple comparison of gene expression, measured in fold [ Time Frame: at time of biopsy taking ]
    Expression profile for proliferative and invasive genes in adenomyotic tissue and surrounding stromal cells compared to healthy individuals, in fold

  2. Frequency of complications related to biopsy taking in percent (%) [ Time Frame: through 1 hour after biopsytaking ]
  3. Serum levels of prolactin in mU/L [ Time Frame: at time of hysterectomy ]
    Serum levels of prolactin

  4. Serum level of ER, in nmol/L [ Time Frame: at time of hysterectomy ]
    Serum level of estrogen.

  5. Serum levels of FSH in U/L [ Time Frame: at time of hysterectomy ]
    Levels of follicle stimulating hormone.

  6. Serum levels of AMH in pmol/L [ Time Frame: at time of hysterectomy ]
    Levels of Anti-Mullerian hormone.

  7. Serum levels of LH in U/L [ Time Frame: at time of hysterectomy ]
    Levels of luteinizing hormone.

  8. difference hormone serum-levels in fold [ Time Frame: at time of hysterectomy ]
    Comparison of serum-levels of PRL, FSH, AMH, LH and ER in patients with and without adenomyosis


Biospecimen Retention:   Samples With DNA
whole blood and biopsies from uterine myometria and uterine endometria


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Ages Eligible for Study:   30 Years to 50 Years   (Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   Yes
Sampling Method:   Non-Probability Sample
Study Population
women referred to our clinic and volunteering to participate
Criteria

Inclusion Criteria:

Premenopausal women aged 30 - 50 years old scheduled for vaginal, abdominal or laparoscopic total hysterectomy one or more of the following clinical symptoms:

  • bleeding disorders (menorrhagia, irregular bleeding, hypermenorrhoea),
  • chronic pelvic pain,
  • dysmenorrhoea,
  • or dyspareunia junction zone definable

Exclusion Criteria:

  • postmenopausal women,
  • pregnancy
  • gynecological cancer
  • GnRH analog therapy or systemic hormone therapy in the last three months prior to hysterectomy
  • junctional zone not identifiable

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02197923


Locations
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Norway
Gynecological department, Oslo University Hospital, Ullevål
Oslo, Norway, 0382
Sponsors and Collaborators
Oslo University Hospital
University of Oslo
Helse Sor-Ost
Investigators
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Study Chair: Erik Qvigstad, PhD, MD Oslo University Hospital, Ullevål
Principal Investigator: Tina Tellum, MD Oslo University Hospital

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Responsible Party: Tina Tellum, MD, Oslo University Hospital
ClinicalTrials.gov Identifier: NCT02197923     History of Changes
Other Study ID Numbers: 2014/637b
First Posted: July 23, 2014    Key Record Dates
Last Update Posted: August 20, 2019
Last Verified: August 2019
Keywords provided by Tina Tellum, Oslo University Hospital:
Menorrhagia
Dysmenorrhea
Pelvic pain
expression profiling
uterine biopsies
serum hormones
Additional relevant MeSH terms:
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Adenomyosis
Uterine Diseases
Genital Diseases, Female