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
Conditions: Heavy Menstrual Bleeding
Sponsor: Bakirkoy Dr. Sadi Konuk Research and Training Hospital

Date: 01.01.2020 
The Effect of Estradiol Valerate, Lng-IUD, and Micronized Progesterone Treatment On 
Health Quality of Patients with Heavy Menstrual Bleeding 
Women who were admitted and treated for heavy menstrual bleeding 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 assesse 
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…) 
Statistical analysis 
Data analysis was performed by using SPSS (IBM SPSS Statistics for Windows, Version 20.0. 
Armonk, NY: IBM Corp.). A one-sample Kolmogorov–Smirnov test was performed to analyze 
the distribution of clinical variables. The frequency and percentage of the categorical variables 
and the mean, standard deviation of the continuous and ordinal variables were presented. The 
study groups were compared using One-way analysis of variance (ANOVA) test for parametric 
variables and the Kruskal Wallis H test for the non-parametric variables. Wilcoxon signed rank 
test was used for the comparison of the BAI and FSFI scores at the first visit and second visits. 
For all calculations, a p-value of <0.05 was considered statistically significant.