Essay: ORAL ORMELOXIFENE AND LEVONORGESTREL IUCD IN MANAGEMENT OF DYSFUNCTIONAL UTERINE BLEEDING

ABSTRACT
INTRODUCTION: Dysfunctional uterine bleeding constitutes a considerable problem for many women causing discomfort and decreased quality of life. About 10-15% of women experience episodes of DUB at sometime during the reproductive years of their lives. Annually 5-19% of women seek medical care. It accounts for more than 25% of all hysterectomies. A wide range of treatment modalities are available.
OBJECTIVES: To study efficacy of oral ormeloxifene and levonorgesterol IUCD in terms of blood loss, endometrial thickness, hemoglobin concentration and to evaluate side effects in DUB.
METHODS: 80 women presenting with dysfunctional uterine bleeding were allocated to 2 equal groups, group1: received 60mg oral ormeloxifene twice a week for 12 weeks and once a week for next 12weeks. Group2: received levonorgesterol IUCD. The primary outcomes were reduction in menstrual blood loss( measured by fall in PBAC score), rise in hemoglobin levels, decrease in endometrial thickness. The follow up was done at 3rd and 6th month.
RESULTS: This study shows significant reduction in PBAC scores with use of ormeloxifene (P=<0.001) and also with Levonorgestrel IUCD (P=<0.001), hence reduction in blood loss. Significant increase in hemoglobin concentration with ormeloxifene (P=<0.001) and levonorgestrel IUCD (P=0.002) and decrease in endometrial thickness with ormeloxifene (P=<0.001) and levonorgestrel IUCD (P=<0.001). No statistical significant between the two groups.
CONCLUSION: Both ormeloxifene and levonorgestrel IUCD are equally efficacious and safe. Ormeloxifene is preferred for treatment of DUB as it is easy to administer and cheap compared to levonorgestrel IUCD which is costly and with few side effects like spotting, which makes patient apprehensive.
KEYWORDS: Dysfunctional uterine bleeding, ormeloxifene, levonorgestrel IUCD, PBAC.
INTRODUCTION
• DUB is defined as a state of abnormal uterine bleeding in the absence of recognizable pelvic pathology, pregnancy or generalized bleeding disorder and most commonly affects the women of reproductive age group. [1]
• Dysfunctional uterine bleeding constitutes a considerable problem for many women causing discomfort and decreased quality of life. About 10-15% of women experience episodes of dysfunctional uterine bleeding at sometime during the reproductive years of their lives. It is a common cause of iron deficiency anaemia in healthy fertile female[3].
• Annually 5-10% of women of reproductive age seek medical care for DUB which negatively impacts quality of life. Over all it accounts for 6.2% of genitourinary disease reporting to outpatient department and may account for more than 25% of all hysterectomies [4]
• A wide range of treatment modalities are available for dysfunctional uterine bleeding which include medical therapy and surgical interventions. Pharmacological management can be hormonal or non hormonal. Non hormonal drugs like NSAID’S, ethamsylate and antifibrinolytics have been found to be highly effective. Hormonal agents include progestins, combined OCP’s, danazol, GnRH agonists, latest SERMs, oestrogens, sometimes androgens, Levonorgestrel IUCD.
• RCOG recommends beginning with medical management before resorting to surgical intervention[4].
• Medical management has always been the first therapeutic option to be tried as it is less complicative, less morbidity, and economical. For medical management many drugs are available. Each drug has its own advantages, disadvantages, side effects.
• Ormeloxifene a non steroidal selective estrogen receptors modulator and has been used for past 20years as an oral contraceptive. It is good option for menorrhagia leading to 77-85% reduction in menstrual blood loss and causes amenorrhea in 17-42% patients.[1]
• Ormeloxifene is a benzopyram SERM, which blocks the cytosol receptors by its competitive binding over estradiol. It is primarily a potent estrogen antagonist and demonstrates a suppressive or a stimulatory effect on gonadotropin release. It normalizes the bleeding from uterine cavity by regularizing the expression of estrogen receptors on the endometrium and hence used in dysfunctional uterine bleeding.[4] It is cheap, effective and has good patient compliance.
• One minimally invasive procedure for control of menorrhagia is levonorgesterol intrauterine device. The Levonorgestrol ICUD has a reservoir containing 52mg levonorgestrol mixed with polydimethylsiloxane, which controls the rate of hormone release. Menstrual blood loss in women with heavy menstrual bleeding can be reduced by 75-95% due to progestin induced decidualization of the endometrium. Levonorgestrol IUCD is an attractive option for ovulatory women with heavy menstrual bleeding.
• Hysterectomy should be the last resort in management of dysfunctional uterine bleeding, because of the morbidity, mortality associated with the surgical procedure, economic burden, need for rest.
MATERIALS AND METHODS: A comparative study was conducted in 80 patients ( 40 into ormeloxifene group and 40 into levonorgestrel group) of reproductive age group attending the outpatient department or admitted in-patients in department of obstetrics and gynecology at Sri Siddhartha Medical College and Research Centre, Tumkur, during the period of November 2016 to April 2018.
INCLUSION CRITERIA: Women of reproductive age group diagnosed with dysfunctional uterine bleeding.
EXCLUSION CRITERIA: Patient with pelvic pathology-uterine fibroid, PID, adenomyosis, endometriosis, chronic cervicitis and malignancies of uterus / cervix /ovary / vagina / complex endometrial hyperplasia with atypia and platelet disorders, coagulopathy, previous history of thrombosis,Pregnancy and lactation, PCOS, Hypothyroidism, Chronic cervicitis, Jaundice, hepatic dysfunction, Tb, renal impairment, Hypersensitivity to drug were excluded.
An informed written consent from all the women who were included in the study were taken. A detailed history, complete physical examination, routine investigations like hemoglobin, bleeding time, clotting time, platelet, RBS, thyroid function tests, liver function test, transvaginal USG to rule out pelvic pathology and to measure endometrial thickness were done to all patients.
The recruitment of the participants to the study groups were done after explaining about the merits and demerits of Ormeloxifene and LNG-IUCD.
As by their choices, the subjects were allocated into 2 groups. Group ormeloxifene and Group levonorgestrel IUCD.
For group ormeloxifene , the drug ormeloxifene was administered orally in the form of tablet (60mg) twice a week, for first 12 weeks and then once a week for another 12 weeks and for other LEVONORGESTEROL intra uterine contraceptive device was inserted. They were advised to attend four weekly or earlier if required to OPD for follow up.
Blood hemoglobin levels and endometrial thickness (TVS) were measured initially, at 3 months and at the end of the study (6 months).
A well designed questionnaire , recorded the subjective assessment of menstrual flow and dysmenorrhea and/ or any side effects of drugs, pictorial blood loss assessment chart (PBAC) score was recorded.
The main outcome measures will be:​
1) Pre treatment and post treatment assessment of menstrual blood loss objectively by pictorial blood loss assessment chart (PBAC) scores .
2) Blood haemoglobin levels.
3) Endometrial thickness (Trans vaginal scan).
RESULTS
Table 1: Age, locality, parity distribution of patients studied in ormeloxifene and levonorgestrel IUCD group
PARAMETERS
ORMELOXIFENE
LNG IUCD
TOTAL
P VALUE
AGE (Mean±SD)
38.53±3.81
40.50±2.88
39.51±3.50
0.011
LOCALITY
URBAN
11(27.5%)
25(62.5%)
36(45%)
0.002
RURAL
29(72.5%)
15(37.5%)
44(55%)
PARITY
NULLIPAROUS
0(0%)
0(0%)
0(0%)
MULTIPARA
40(100%)
40(100%)
80(100%)
<0.001
​​P=0.011*, Significant, Student t test
Table 1 shows statistics of age distribution, locality and parity of subjects in both ormeloxifene and levonorgestrel IUCD groups. The mean age of study population in Group Ormeloxifene was 38.53±3.81, and in LNG IUCD group was 40.50±2.88. Majority of women in ormeloxifene group were from rural locality (72.5%) and in LNG IUCD group were from urban locality (62.5%). All 80 women in both the groups were multiparous.
Table 2: Pictorial blood loss assessment chart score, hemoglobin concentration, endometrial thickness in both the groups.
PARAMETERS
GROUPS
BEFORE TREATMENT
AFTER 3 MONTHS TREATMENT
AFTER 6 MONTHS TREATMENT
P VALUE
PBAC
ORMELOXIFENE
174.20±56.93
22.87±29.90
3.74±10.99
<0.001
LNG IUCD
172.08±41.50
11.76±22.72
3.97±10.96
<0.001
ENDOMETRIAL THICKNESS
ORMELOXIFENE
9.32±3.10
7.04±1.67
5.84±0.99
<0.001
LNG IUCD
10.02±3.15
6.99±1.04
5.43±1.21
<0.001
HEMOGLOBIN
ORMELOXIFENE
10.22±1.36
10.61±1.15
11.03±1.02
<0.001
LNG IUCD
9.78±1.29
10.14±1.96
10.64±1.99
0.002
Student t test (Two tailed, Independent). PBAC= pictorial blood loss assessment chart, LNG= Levonorgestrel
Table 2: shows PBAC scores, endometrial thickness, haemoglobin concentration before treatment, 3 months and 6 months after treatment in ormeloxifene and levonorgestrel IUCD groups. PBAC scores is statistically reduced in both ormeloxifene group (P=<0.001) and LNG IUCD group (P=<0.001). Table2 shows statistically significant reduction in endometrial thickness after 6 months of treatment in ormeloxifene group (P=<0.001) and LNG IUCD group (P=<0.001). Also shows increase in haemoglobin concentration after 6 months of treatment in ormeloxifene group (P=<0.001) and LNG IUCD group (P=0.002).
Table 3: Outcome distribution in two groups of patients studied
Outcome
Group ORMELOXIFENE
Group LNG IUCD
Total
Amenorrhea
30(75%)
32(80%)
62(77.5%)
Symptomatically improved
8(20%)
4(10%)
12(15%)
Dropout
0(0%)
3(7.5%)
3(3.8%)
Hysterectomy
2(5%)
1(2.5%)
3(3.8%)
Total
40(100%)
40(100%)
80(100%)
​​P=0.185, Not Significant, Fisher Exact Test
Table3 shows the outcome of 80 patients (40 in each group) included in the study.
Out of 40 patients in group Ormeloxifene, 30 patients attained amenorrhea, 8 patients symptomatically improved, 2 patients underwent hysterectomy.
Out of 40 patients in group LNG IUCD, 32 patients attained amenorrhea, 4 patients symptomatically improved, 3 patients lost to follow up, 1 patient underwent hysterectomy.
DISCUSSION
Medical management has always been the first therapeutic option to be tried and if the results fail, one can resort to surgical interventions. Medical treatment of menorrhagia should aim to relieve symptoms, improve quality of life and to avoid the risk of surgery.
The present study was conducted to evaluate the efficacy and safety of oral ormeloxifene and levonorgesterol IUCD in the management of dysfunctional uterine bleeding.
Our study included patients with menorrhagia in the age group 31-50years attending the outpatient department or admitted as inpatients in the department of obstetrics and gynecology at Sri Siddhartha Medical College and Research Centre, Tumkur.
Patients were divided into 2 groups of ormeloxifene and levonorgesterol IUCD. Patients were followed up for 6 months. Pre and post treatment outcome measures in both groups studied were as follows.
– Pre treatment and post treatment assessment of menstrual blood loss objectively by pictorial blood loss assessment chart.
– Blood hemoglobin levels
– Endometrial thickness ( transvaginal scan).
Among 80 patients included in the study, two groups contained 40 patients each. Out of 40 who were treated with oral ormeloxifene, 30 patients attained amenorrhea, 2 patients underwent hysterectomy, 8 patients symptomatically improved. Out of 40 patients treated with levonorgesterol IUCD , 32 patients attained amenorrhea, 1 patient underwent hysterectomy, 4 patients symptomatically improved and 3 patients lost to follow up.
Amenorrhea in our study was defined as absence of bleeding for 3 consecutive cycles.
Symptomatically improved patients = patients in whom cycles were 45-60 days but there was significant reduction in bleeding, reduction in PBAC score, reduction in endometrial thickness and increase in hemoglobin percentage.
In this study, the patients who are treated with oral ormeloxifene shows there was significant reduction in menstrual blood loss as assessed by fall in PBAC score (Table2). The mean pretreatment menstrual blood loss (PBAC score) was 174.20±56.93 which reduced to 22.87±29.90 at 3 months and 3.74±10.99 at 6 months with treatment. There was significant reduction in menstrual blood loss in patients with ormeloxifene. The results of this study (table-2) suggests that the rise in haemoglobin level at the end of 6 months of treatment was 11.03±1.02 compared to the pretreatment level of 10.22±1.36. The rise in haemoglobin level at the end of 6 months was significant. The mean endometrial thickness (Table-2) in the pretreatment group was 9.32±3.10 and there was decrease in mean endometrial thickness at the end of 6 months 5.84±0.99 of treatment with oral ormeloxifene.
Dhananjaya et al[6] studied 35 patients with dysfunctional uterine bleeding and found a statistically significant increase in haemoglobin concentration (8.26 to 10.59g/dl, P<0.001) and statistically significant decrease in endometrial thickness (9.83 to 4.89, P< 0.001) after 6 months of treatment with ormeloxifene.
Neha et al[5] studied 50 patients and found a PBAC score ranging from 123 – 643 pretreatment and 0-75 at the end of 6 month, decrease in endometrial thickness (11.35 to 8.13), rise in haemoglobin level (9.04 to 10.86) after 6 months of treatment with ormeloxifene.
In this study, the patients who are treated with levonorgesterol IUCD shows there was significant reduction in menstrual blood loss as assessed by fall in PBAC score (Table2). The mean pretreatment menstrual blood loss (PBAC score) was 172.08±41.50 which reduced to 11.76±22.72 at 3 months and 3.97±10.96 at 6 months with treatment. There was significant reduction in menstrual blood loss in patients with levonorgesterol IUCD. The results of this study (table-2) suggests that the rise in haemoglobin level at the end of 6 months of treatment was 10.64±1.99 compared to the pretreatment level of 9.78±1.29. The rise in haemoglobin level at the end of 6 months was significant. The mean endometrial thickness (Table-2) in the pretreatment group was 10.02±3.15 and there was decrease in mean endometrial thickness at the end of 6 months 5.43±1.21 of treatment with levonorgesterol IUCD.
Shalini et al[7] studied 40 patients with dysfunctional uterine bleeding and found a statistically significant increase in haemoglobin concentration (9.84 to 10.06g/dl) and fall in mean PBAC score of 199.45±30.23 before treatment to 53.18±14.73 after 6 months of treatment with levonorgesterol IUCD.
Taru G et al[2] studied 70 women with levonorgesterol IUCD insertion for heavy menstrual bleeding which resulted in reduction in menstrual blood loss to 79% after 6 months of insertion. Improvement in haemoglobin levels from 8.16 to 9.35±0.7g% by 6 months.
There are no much studies conducted comparing oral ormeloxifene and levonorgesterol IUCD in the management of dysfunctional uterine bleeding.
In our study, no major side effects were seen with both oral ormeloxifene and levonorgesterol IUCD. Only 4 patients out of 40 treated with levonorgesterol IUCD had history of spotting pervagina.
In our study both oral ormeloxifene and levonorgesterol IUCD had significant reduction in pictorial blood loss assessment chart score , decrease in endometrial thickness and increase in haemoglobin concentration after treatment for 6 months in patients with dysfunctional uterine bleeding.
Both oral ormeloxifene and levonorgestrel IUCD treatment modalities were safe. Both were efficacious in treatment of dysfunctional uterine bleeding. No statistical significant differences between two treatment modalities were found.
CONCLUSION
Heavy menstrual bleeding or dysfunctional uterine bleeding is a very common gynecological problem. The options in management are wide and varied and often difficult to make a right choice as each one has their own merits and demerits. In the present day practice, hysterectomy has become obsolete for dysfunctional uterine bleeding and other minimally invasive techniques are costly. Hence medical management has become a choice of treatment in dysfunctional uterine bleeding. Most of the western guidelines recommend Levonorgestrel IUCD as first line of treatment. From our study we found both Ormeloxifene and Levonorgestrel IUCD are equally efficacious and safe. Hence both can be used for treatment particularly in perimenopausal women. Ormeloxifene is easy to administer and cheap. Levonorgestrel IUCD is costly but one time administration with few side effects like spotting, which makes patient apprehensive. Hence Ormeloxifene which is equally effective and cheap can be recommended for the treatment of dysfunctional uterine bleeding.