Quality of Life in Premenopausal Women With Heavy Menstrual Bleeding

• Sponsor: Bakirkoy Dr. Sadi Konuk Research and Training Hospital (Other)
• Overall Status: Completed
• CT.gov ID: NCT03368898
• Collaborator: (none)
• Enrollment: 104
• Location: 1
• Actual Duration (Months): 35.9
• Patients Per Site Per Month: 2.9

Study Details

Study Description

Brief Summary

Heavy menstrual bleeding or menorrhagia, is a common problem on women's lives and can burden both patients and health care systems. HMB is defined as cyclic heavy vaginal bleeding. Hormonal treatment of heavy menstrual bleeding (HMB) is also endorsed as the first line treatment in several international guidelines. The effects of these therapies on bleeding related quality of life are not well known. The aim of the present study is compare the effect of Estradiol Valerate/Dienogest (E2V/DNG), Levonorgestrel-Intrauterine Device (LNG-IUD) and oral micronized progesterone treatment on bleeding pattern, cycle control, menopausal symptoms and patient satisfaction of women with HMB.

Condition or Disease	Intervention/Treatment	Phase
Heavy Menstrual Bleeding

Detailed Description

Women who were admitted and treated for HMB were asked to participate in this comparative study. Women were eligible for entry if they had self-described heavy menstrual bleeding, had a regular cycle, had completed their family and were 40-50 years old at initial assessment.

After a thorough physical examination and ultrasonographic evaluation, all women underwent endometrial biopsy before the study by using a Pipelle endometrial suction curette to rule out any organic endometrial pathology. Blood samples were analysed to test for hemoglobin (Hb), hematocrit (Hct), ferritin, serum iron and iron-binding capacity and coagulation tests such as prothrombin time and activated partial thromboplastin time.

The study was approved by the Institutional Review Board and Local Ethics Committee. After they gave written informed consent, patients who fulfilled eligibility criteria were recruited to one of the following 3 groups:

Group 1: Women who were treated with estradiol valerate/dienogest regimen for heavy menstrual bleeding. 28 days of E2V/DNG was administered using a dynamic dosing regimen. (E2V 3 mg on days 1-2, E2V 2 mg/DNG 2 mg on days 3-7, E2V 2 mg/DNG 3 mg on days 8-24, E2V 1 mg on days 25-26 and placebo on days 27-28).

Group 2: Women who were treated with LNG-IUD for heavy menstrual bleeding. LNG-IUD is containing 52 mg levonorgestrel at initial placement and releases 20 microgram levonorgestrel per day. This is approved for 5 years of use by the US FDA for treatment of HMB.

Group 3: Women who were treated with oral Micronized Progesterone 200 mg for heavy menstrual bleeding. Cyclic, luteal-phase administration of progestin remained a widely used but little research treatment strategy for HMB for several decades.

None of the recruited patients were not prescribed oral iron preparations and patients who were symptomatic because of anemia (hb<10 mg/dl) were excluded.

Baseline characteristics of women are age (years), body mass index, parity, current smoker, days of bleeding, length of cycle (days), number of days of heavy bleeding, number of days of painful bleeding, unable to leave house on heaviest days, number of days housebound, number of nights disturbed, Pictorial Bleeding Assessment Chart (PBAC) score (A monthly score of 100 or more on this chart is significantly associated with heavy menstrual bleeding of more than 80 ml per cycle, as measured by the alkaline haematin method), endometrial thickness at time of treatment (mm), uterine size (length x width).

The Exclusion criteria are

1. ultrasound abnormalities (submucosal fibroids, intramural fibroids greater than 3 cm in diameter, large subserosal fibroids, endometrial polyps);

2. laboratory abnormalities (follicle stimulating hormone level higher than 40 iu/l, adverse endometrial histology)

3. hysteroscopic abnormalities (submucosal fibroids, endometrial polyps),

4. incidental adnexal abnormality on ultrasound,

5. severe intermenstrual bleeding, severe dysmenorrhoea, severe premenstrual pain, chronic pelvic pain,

6. medical contraindications to either study treatment,

7. previous endometrial ablation or resection,

8. uninvestigated postcoital bleeding

9. untreated abnormal cervical cytology.

10. pregnancy; lactation; occurrence of <3 menstrual cycles following childbirth, abortion or lactation;

11. current use of an intrauterine device; hypersensitivity to any of the study drug ingredients and known or suspected malignant or premalignant disease.

12. systemic diseases like hypertension, diabetes, thyroid diseases or coronary artery diseases; and history of previous medication for menorrhagia

13. using anticoagulant drugs

Women who were recruited the study will be assessed at 1,3 and 6 months with Hot Flush Rating Scale (HFRS), Menopause Rating Scale (MRS), menorrhagia multi-attribute scale (MM-AS), pictorial bleeding assessment chart and blood sample analysis.

The primary outcomes assessed

1. Hot flush rating scale: Measures included the HFRS, a self-report measure of frequency and problem rating of Hot Flushes/Night Sweats over the past week. Problem rating is calculated as the mean of the scores on three ten-point scales assessing the extent to which Hot Flushes/Night Sweats are problematic, distressing and causing interference in daily life. Scores for the problem rating range between 1 and 10, with higher scores indicating more problematic Hot Flushes/Night Sweats. The HFRS has been found to have reasonable test-retest reliability and good concurrent validity.

2. Menopause rating scale: The Menopause Rating Scale (MRS) is a questionnaire that assesses the presence and intensity of 11 menopausal symptoms. These are grouped into three subscales: the somatic subscale: assessing hot flushes/sweating, heart discomfort, sleeping problems, and muscle and joint discomfort (items 1-3 and 4 respectively); the psychological subscale: assessing depressive mood, irritability, anxiety, and physical and mental exhaustion (items 4-7 respectively); and the urogenital subscale: assessing sexual problems, bladder problems and vaginal dryness (items 8- 10, respectively). Each of the 11 items can be rated by the participant from 0 (not present) to 4 (1 ¼ mild, 2 ¼ moderate, 3 ¼ severe and 4 ¼ very severe). The scores obtained for each individual item are summed to provide the corresponding total subscale score. The sum of subscales scores provide the total MRS score. Higher scores are indicative of more severe symptoms. Indeed values above 8 (somatic), 6 (psychological), 3 (urogenital) and 16 (total MRS) were defined as severe.

The secondary outcomes assessed

1. Quality of life as measured by menorrhagia multi-attribute scale: which is designed to measure the effect of menorrhagia on six domains of daily life (practical difficulties, social life, psychological health, physical health, work and daily routine, and family life and relationships). Summary scores, which range from 0 (severely affected) to 100 (not affected)

2. Menstruation, by pictorial bleeding assessment chart

3. Haemoglobin levels were also measured at pre-treatment,1, 3 and 6 months.

4. Adverse event (Breast pain, Headache, Acne, Alopecia, Migraine, Increase in body weight…)

Study Design

• Study Type: Observational [Patient Registry]
• Actual Enrollment: 104 participants
• Observational Model: Other
• Time Perspective: Cross-Sectional
• Official Title: Comparison of Estradiol Valerate (E2V), Levonorgestrel- Intrauterine Device (LNG-IUD) and Oral Micronized Progesterone Therapy on Health-related Quality of Life in Premenopausal Women With Heavy Menstrual Bleeding
• Actual Study Start Date: Jan 1, 2017
• Actual Primary Completion Date: Jun 30, 2018
• Actual Study Completion Date: Dec 30, 2019

Arms and Interventions

Arm	Intervention/Treatment
Estradiol valerate Women who were treated with E2V for HMB for 3 months.
LNG-IUD Women who were treated with LNG-IUD for HMB for 4 years.
Micronized Progesterone Women who were treated with Micronized Progesterone for HMB for 3 months.

Outcome Measures

Primary Outcome Measures

1. Hot Flush Frequency Total Score (HFRS) Change [change from initial hot flush frequency score at 6 months]

   Hot flush rating scale (HFRS) is a 5 items subjective tool. The first and second items of this scale are for Hot Flush Frequency Score. Women were asked to provide ratings of the frequency of hot flushes and night sweats in the first and second items. The number of the frequency in the first and second item is summed and this score is the total hot flush frequency score. The minimum Hot Flush Frequency Score is 0 and there is no maximum score to provide. However, the higher scores represent worse outcome. In this study, the Hot Flush Frequency Score is measured and recorded at initial of the treatment and six months of treatment. The change between the initial and six months score is our first primer outcome.

2. Total Menopause Rating Scale (MRS) Score Change [change from initial menopause rating scale score at 6 months]

   Menopause Rating Scale (MRS) is a questionnaire that assesses the presence and intensity of 11 menopausal symptoms. These are grouped into three subscales: the somatic subscale, the psychological subscale and the urogenital subscale. Each of the 11 items can be rated by the participant from 0 (not present) to 4 (very severe). The scores obtained for each individual item are summed to provide the corresponding total subscale score. The sum of subscales scores provide the total MRS score. Higher scores are indicative of more severe symptoms. Minimum total MRS score is 0 and maximum total MRS score is 44.

Secondary Outcome Measures

1. Menopause Multi-Attribute Score Change on Menopause Multi-Attribute Scale. [change from initial menopause multi-attribute score at 6 months]

   This is measured by menorrhagia multi-attribute scale; which is designed to measure the effect of menorrhagia on six domains of daily life (practical difficulties, social life, psychological health, physical health, work and daily routine, and family life and relationships). Scores range from 0 (severely affected) to 100 (not affected). Higher scores represent a better outcome.

2. Pictorial Bleeding Assessment Score Change [change from initial Pictorial bleeding assessment score at 6 months]

   The pictorial blood assessment chart (PBAC) consists of a series of diagrams representing lightly, moderately, and heavily soiled towels and tampons. The numbers at the top of the chart represent the day of menstruation. The women are instructed to insert a mark in the appropriate box at the time each towel and/or tampon is discarded. After completion, the woman returns the chart during her next appointment to the clinic. The chart is scored using the scoring system. A baseline score is established and then at six months of treatment, the score is assessed again. Change from the initial score at 6 months of treatment is recorded as a secondary outcome. Decreasing values are considered to be a better outcome.

3. Hemoglobin Value Change [change from initial hemoglobin values at 6 months]

   Blood sample analysis for hemoglobin values is performed before the treatment and at six months of treatment.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 40 Years to 50 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• women who self described heavy menstrual bleeding

• women who completed their family

• have cyclic menstruation

• 40 to 50 years old

Exclusion Criteria:

1. ultrasound abnormalities (submucosal fibroids, intramural fibroids greater than 3 cm in diameter, large subserosal fibroids, endometrial polyps);

2. laboratory abnormalities (follicle-stimulating hormone level higher than 40 iu/l, adverse endometrial histology)

3. hysteroscopic abnormalities (submucosal fibroids, endometrial polyps),

4. incidental adnexal abnormality on ultrasound,

5. severe intermenstrual bleeding, severe dysmenorrhoea, severe premenstrual pain, chronic pelvic pain,

6. medical contraindications to either study treatment,

7. previous endometrial ablation or resection,

8. uninvestigated postcoital bleeding

9. untreated abnormal cervical cytology.

10. pregnancy; lactation; occurrence of <3 menstrual cycles following childbirth, abortion or lactation;

11. current use of an intrauterine device; hypersensitivity to any of the study drug ingredients and known or suspected malignant or premalignant disease.

12. systemic diseases like hypertension, diabetes, thyroid diseases or coronary artery diseases; and history of previous medication for menorrhagia

13. using anticoagulant drugs

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Bakirkoy Dr. Sadi Konuk Training and Research Hospital	Istanbul		Turkey	34147

Sponsors and Collaborators

• Bakirkoy Dr. Sadi Konuk Research and Training Hospital

Investigators

• Study Director: cihan kaya, Bakırkoy Dr. Sadi Konuk Training and Research Hospital

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jan 1, 2020

More Information

Publications

None provided.

• Responsible Party: Ismail Alay, principal investigator, Bakirkoy Dr. Sadi Konuk Research and Training Hospital
• ClinicalTrials.gov Identifier: NCT03368898
• Other Study ID Numbers: HMBSYMPTOM
• First Posted: Dec 11, 2017
• Last Update Posted: Sep 24, 2020
• Last Verified: Sep 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No
• Additional relevant MeSH terms: Menorrhagia; Hemorrhage

Study Results

Participant Flow

Arm/Group Title	Estradiol Valerate	LNG-IUD	Micronized Progesterone
Arm/Group Description	Women who were treated with Estradiol valerate for Heavy Menstrual Bleeding for 3 months.	Women who were treated with Levonorgestrel Intrauterine Device (LNG-IUD) for Heavy Menstrual Bleeding for 4 years.	Women who were treated with Micronized Progesterone for Heavy Menstrual Bleeding for 3 months.
Period Title: Overall Study
STARTED	37	33	34
COMPLETED	37	33	34
NOT COMPLETED	0	0	0

Baseline Characteristics

Arm/Group Title	Estradiol Valerate	LNG-IUD	Micronized Progesterone	Total
Arm/Group Description	Women who were treated with Estradiol valerate for Heavy Menstrual Bleeding for 3 months.	Women who were treated with Levonorgestrel Intrauterine Device LNG-IUD for Heavy Menstrual Bleeding for 4 years.	Women who were treated with Micronized Progesterone for Heavy Menstrual Bleeding for 3 months.	Total of all reporting groups
Overall Participants	37	33	34	104
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	44.7 (4.7)	45 (4.6)	45.4 (4.7)	45 (4.6)
Sex: Female, Male (Count of Participants)
Female	37 100%	33 100%	34 100%	104 100%
Male	0 0%	0 0%	0 0%	0 0%
Race and Ethnicity Not Collected (Count of Participants)
Count of Participants [Participants]	0 0%

Outcome Measures

1. Primary Outcome

Title	Hot Flush Frequency Total Score (HFRS) Change
Description	Hot flush rating scale (HFRS) is a 5 items subjective tool. The first and second items of this scale are for Hot Flush Frequency Score. Women were asked to provide ratings of the frequency of hot flushes and night sweats in the first and second items. The number of the frequency in the first and second item is summed and this score is the total hot flush frequency score. The minimum Hot Flush Frequency Score is 0 and there is no maximum score to provide. However, the higher scores represent worse outcome. In this study, the Hot Flush Frequency Score is measured and recorded at initial of the treatment and six months of treatment. The change between the initial and six months score is our first primer outcome.
Time Frame	change from initial hot flush frequency score at 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Estradiol Valerate	LNG-IUD	Micronized Progesterone
Arm/Group Description	Women who were treated with Estradiol valerate for Heavy Menstrual Bleeding for 3 months.	Women who were treated with Levonorgestrel Intrauterine Device (LNG-IUD) for Heavy Menstrual Bleeding for 4 years.	Women who were treated with Micronized Progesterone for Heavy Menstrual Bleeding for 3 months.
Measure Participants	37	33	34
Mean (Standard Deviation) [score on a scale]	9.3 (26.4)	8.8 (20.5)	12.7 (30.3)

2. Primary Outcome

Title	Total Menopause Rating Scale (MRS) Score Change
Description	Menopause Rating Scale (MRS) is a questionnaire that assesses the presence and intensity of 11 menopausal symptoms. These are grouped into three subscales: the somatic subscale, the psychological subscale and the urogenital subscale. Each of the 11 items can be rated by the participant from 0 (not present) to 4 (very severe). The scores obtained for each individual item are summed to provide the corresponding total subscale score. The sum of subscales scores provide the total MRS score. Higher scores are indicative of more severe symptoms. Minimum total MRS score is 0 and maximum total MRS score is 44.
Time Frame	change from initial menopause rating scale score at 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Estradiol Valerate	LNG-IUD	Micronized Progesterone
Arm/Group Description	Women who were treated with Estradiol valerate for Heavy Menstrual Bleeding for 3 months.	Women who were treated with Levonorgestrel Intrauterine Device (LNG-IUD) for Heavy Menstrual Bleeding for 4 years.	Women who were treated with Micronized Progesterone for Heavy Menstrual Bleeding for 3 months.
Measure Participants	37	33	34
Mean (Standard Deviation) [score on a scale]	-0.4 (6.5)	-2.5 (7.4)	-1.4 (4.7)

3. Secondary Outcome

Title	Menopause Multi-Attribute Score Change on Menopause Multi-Attribute Scale.
Description	This is measured by menorrhagia multi-attribute scale; which is designed to measure the effect of menorrhagia on six domains of daily life (practical difficulties, social life, psychological health, physical health, work and daily routine, and family life and relationships). Scores range from 0 (severely affected) to 100 (not affected). Higher scores represent a better outcome.
Time Frame	change from initial menopause multi-attribute score at 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Estradiol Valerate	LNG-IUD	Micronized Progesterone
Arm/Group Description	Women who were treated with Estradiol valerate for Heavy Menstrual Bleeding for 3 months.	Women who were treated with Levonorgestrel Intrauterine Device (LNG-IUD) for Heavy Menstrual Bleeding for 4 years.	Women who were treated with Micronized Progesterone for Heavy Menstrual Bleeding for 3 months.
Measure Participants	37	33	34
Mean (Standard Deviation) [score on a scale]	25.2 (31.1)	31.0 (26.7)	22.8 (26.7)

4. Secondary Outcome

Title	Pictorial Bleeding Assessment Score Change
Description	The pictorial blood assessment chart (PBAC) consists of a series of diagrams representing lightly, moderately, and heavily soiled towels and tampons. The numbers at the top of the chart represent the day of menstruation. The women are instructed to insert a mark in the appropriate box at the time each towel and/or tampon is discarded. After completion, the woman returns the chart during her next appointment to the clinic. The chart is scored using the scoring system. A baseline score is established and then at six months of treatment, the score is assessed again. Change from the initial score at 6 months of treatment is recorded as a secondary outcome. Decreasing values are considered to be a better outcome.
Time Frame	change from initial Pictorial bleeding assessment score at 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Estradiol Valerate	LNG-IUD	Micronized Progesterone
Arm/Group Description	Women who were treated with Estradiol valerate for Heavy Menstrual Bleeding for 3 months.	Women who were treated with Levonorgestrel Intrauterine Device (LNG-IUD) for Heavy Menstrual Bleeding for 4 years.	Women who were treated with Micronized Progesterone for Heavy Menstrual Bleeding for 3 months.
Measure Participants	37	33	34
Mean (Standard Deviation) [score on a scale]	-113 (61.6)	-120.7 (51.2)	-112.5 (54.8)

5. Secondary Outcome

Title	Hemoglobin Value Change
Description	Blood sample analysis for hemoglobin values is performed before the treatment and at six months of treatment.
Time Frame	change from initial hemoglobin values at 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Estradiol Valerate	LNG-IUD	Micronized Progesterone
Arm/Group Description	Women who were treated with Estradiol valerate for Heavy Menstrual Bleeding for 3 months.	Women who were treated with Levonorgestrel Intrauterine Device (LNG-IUD) for Heavy Menstrual Bleeding for 4 years.	Women who were treated with Micronized Progesterone for Heavy Menstrual Bleeding for 3 months.
Measure Participants	37	33	34
Mean (Standard Deviation) [mg/dL]	0.5 (1.2)	0.09 (1.4)	0.03 (1.4)

Adverse Events

Time Frame	12 months
Adverse Event Reporting Description	There was no adverse event.
Arm/Group Title	Estradiol Valerate		LNG-IUD		Micronized Progesterone
Arm/Group Description	Women who were treated with Estradiol valerate for Heavy Menstrual Bleeding for 3 months.		Women who were treated with Levonorgestrel Intrauterine Device (LNG-IUD) for Heavy Menstrual Bleeding for 4 years.		Women who were treated with Micronized Progesterone for Heavy Menstrual Bleeding for 3 months.
All Cause Mortality
	Estradiol Valerate		LNG-IUD		Micronized Progesterone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/37 (0%)		0/33 (0%)		0/34 (0%)
Serious Adverse Events
	Estradiol Valerate		LNG-IUD		Micronized Progesterone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/37 (0%)		0/33 (0%)		0/34 (0%)
Other (Not Including Serious) Adverse Events
	Estradiol Valerate		LNG-IUD		Micronized Progesterone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/37 (0%)		0/33 (0%)		0/34 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.