|Year : 2019 | Volume
| Issue : 2 | Page : 87-92
A comparative study of norethisterone and combined oral contraceptive pill in the treatment of dysfunctional uterine bleeding
Sayantan Sen1, Tapan Kumar Mandal1, Arijit Dutta1, Himel Mondal2, Tufan Khalua1
1 Department of Gynecology and Obstetrics, Burdwan Medical College and Hospital, Burdwan, West Bengal, India
2 Department of Physiology, Fakir Mohan Medical College and Hospital, Balasore, Odisha, India
|Date of Submission||20-Jun-2018|
|Date of Decision||12-Jul-2018|
|Date of Acceptance||15-Aug-2018|
|Date of Web Publication||23-May-2019|
Department of Physiology, Fakir Mohan Medical College and Hospital, Balasore - 756 019, Odisha
Source of Support: None, Conflict of Interest: None
Background: A significant percentage of women in India suffer from dysfunctional uterine bleeding (DUB), which has a negative impact on physical and social life. Norethisterone and low-dose combined oral contraceptive (COC) pills are used in the treatment of DUB. Aim: The aim of this study was to compare the efficacy and safety of norethisterone and low-dose COC pills in reduction of blood loss in DUB. Materials and Methods: A prospective randomized interventional study was conducted with patients with DUB. Pretreatment pictorial blood loss assessment chart (PBAC) and hemoglobin in blood were obtained from patients. Then, Group I (n = 50) and Group II (n = 50) patients were provided treatment with norethisterone and low-dose COC pills, respectively. Posttreatment PBAC and hemoglobin level in blood was obtained after 6 months of treatment. Improvements in PBAC and hemoglobin level (difference between posttest and pretest value) were compared by unpaired t-test with α = 0.05. Results: Mean age of Group I and Group II patients was 28.62 ± 9.84 and 28.42 ± 10.08 years, respectively. Improvement in PBAC score in patients treated with norethisterone versus low-dose COC pill was −98.62 ± 7.82 versus −96.44 ± 8.74 (P = 0.19). Improvement in hemoglobin level in patients treated with norethisterone versus low-dose COC pill was 2.75 ± 1.06 gm/dL versus 2.71 ± 0.86 gm/dL (P = 0.84). Conclusion: Norethisterone and low-dose COC pills were found to be equally efficacious in reducing bleeding in DUB. Hence, any one of the drugs can be used in the treatment of DUB according to patients' profile. However, considering the side effects, low-dose COC pills may be a better choice.
Keywords: Abnormal uterine bleeding, hemoglobins, menorrhagia, menstruation disturbances, uterine hemorrhage
|How to cite this article:|
Sen S, Mandal TK, Dutta A, Mondal H, Khalua T. A comparative study of norethisterone and combined oral contraceptive pill in the treatment of dysfunctional uterine bleeding. CHRISMED J Health Res 2019;6:87-92
|How to cite this URL:|
Sen S, Mandal TK, Dutta A, Mondal H, Khalua T. A comparative study of norethisterone and combined oral contraceptive pill in the treatment of dysfunctional uterine bleeding. CHRISMED J Health Res [serial online] 2019 [cited 2020 May 27];6:87-92. Available from: http://www.cjhr.org/text.asp?2019/6/2/87/258981
| Introduction|| |
Dysfunctional uterine bleeding (DUB) is excessive uterine bleeding which is not attributed to pregnancy or any detectable uterine or systemic pathology., Patients suffering from DUB commonly complain about heavy menstrual bleeding (HMB), irregular bleeding, spotting between periods, or spotting after sex., About 17.9% of Indian women suffer from DUB.
Diagnosis of DUB depends on detailed history, clinical examination, estimation of blood loss in menstruation along with complete blood count (CBC), ultrasonography and wherever possible hysteroscopy, biopsy, and magnetic resonance imaging., Pictorial blood loss assessment chart (PBAC) is an easy way to estimate blood loss during menstruation by scoring the blood-stained sanitary napkin/towel/pad. Despite criticism, this semi-subjective method is a better method than the subjective method of assessment.,
There are several treatment strategies for DUB according to the cause of the disorder. With an aim to reduce the amount of bleeding and prevent its recurrence, the medical management includes the use of antifibrinolytic drug – tranexamic acid, inhibitor of prostaglandin synthesis – nonsteroidal anti-inflammatory drugs, combined oral contraception pill, progestogen, danazol, and gonadotropin-releasing hormone analogs.,,
Several previous studies have evaluated the efficacy of combined oral contraceptive (COC) pill and ormeloxifene in the treatment of DUB, and both of them were found effective in reduction of menstrual bleeding.,, Studies also reported the comparison between ormeloxifene and norethisterone in the treatment of DUB and found ormeloxifene to be superior in the management of DUB., A study by Patel et al. evaluated the comparative efficacy of COC pill and norethisterone in puberty menorrhagia and reported that norethisterone was more effective than COC pills. The study participants were confined to a limited age group and authors used only hemoglobin and menorrhagia impact questionnaire to evaluate the efficacy. Furthermore, a study by Chauhan et al. evaluated the comparison among norethisterone, ormeloxifene, and COC and reported ormeloxifene to be better than norethisterone and COC. In that study, the authors used hemoglobin and subjective score for assessment of improvement in the status of bleeding.
With this background, the current study was aimed to evaluate the efficacy and safety of norethisterone and COC pills in the reduction of blood loss in patients presenting with DUB. The study was further aimed to recruit patients with wider range of age to get a credible result applied to general population and to use both PBAC and hemoglobin for the evaluation of amount of blood loss.
| Materials and Methods|| |
After obtaining clearance from Clinical Research Ethics Committee, Burdwan Medical College and Hospital (BMC/PG/59), this prospective randomized interventional study was conducted in the Department of Gynecology and Obstetrics, Burdwan Medical College and Hospital, Bardhaman, West Bengal, India, from March 2016 to February 2017.
Minimum sample size estimation
After reviewing related literature, the expected pretreatment and posttreatment PBAC score was considered as 300 and 200, respectively. With an assumption of standard deviation of 100, the minimum sample size was calculated with the formula: N = [(1/q1 + 1/q2) S2 (Zα + Zβ)2] ÷ E 2.
Where N is the total number of patients required, q1 and q2 are the proportion of patients in each group, S is the expected standard deviation, Zα and Zβ are standard normal deviate of α and β, respectively, and E is the effect size (difference between mean of two groups). With α = 0.05 and power of the study as 95%, the estimated sample size was 52. Twenty percent was added to this minimum number which provided a minimum sample size of 62. This sample size was considered minimum for a statistically significant study. In this study, it was aimed to include a total of 50 patients in each group.
This study was conducted with full compliance to the declaration of Helsinki 2013. The informed consent for participation in the study was obtained from the patients whose age was above 18 years (considered adult in India). Where age of the patients was <18 years, consent was obtained both from the patient and their legal guardian. The aim and procedure of the study were described to the patients in detail. Furthermore, the patients were informed that they can discontinue the treatment at any point of time and have full choice not to continue with the study follow-up without stating any reason.
Recruitment of subjects
Patients were recruited from the Outpatient Department of Obstetrics and Gynecology, Burdwan Medical College and Hospital, Bardhaman, West Bengal, India. Patients complaining of HMB were further evaluated for a diagnosis of DUB. Patients who were pregnant and those who presented with severe bleeding which require emergency treatment were not included in the study. A detailed medical and surgical history with history of drug intake was obtained for the presence of any abnormality other than DUB. Clinical general examination and per speculum examination were conducted to exclude any disease or deformity. Then, CBC was carried out to exclude any blood disorder. Thyroid-stimulating hormone was tested for the exclusion of hypo- or hyperthyroidism. Pelvic ultrasonography and Pap smear were examined to further exclusion of any disease. Patients with no detected abnormality other than DUB were then included in the study. The protocol of patient recruitment is shown in [Figure 1].
Pictorial blood loss assessment chart score and hemoglobin estimation
The original PBAC scorecard includes assessment for stained tampon. According to the availability and convenience, in this study, only sanitary pad was used. Hence, a modified PBAC scorecard was made for this study with score for pads and clots. In addition, due to the convenience of Bengali speaking patients, the PBAC card was made in the Bengali language. The scorecard in Bengali is shown in [Figure 2]. Patients were trained to score the card during menstruation by a female expert. A particular brand sanitary pad/napkin with the same absorbance was supplied to all the patients to reduce any error. After one menstrual period, the patients appeared in the hospital with the PBAC score and were recorded in register with a number. Odd number patients were designated in Group I and even number was designated to Group II. This was practiced so that each patient has an equal chance to be selected in two groups.
|Figure 2: Pictorial blood loss assessment chart in Bengali to assess amount of blood loss during menstruation|
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After assigning a patient to a particular group, she undergone test for hemoglobin level in blood. Venous blood was collected from an antecubital vein with aseptic precaution. Then, the blood was transferred for analysis in automated analyzer which uses spectrometric method of hemoglobin estimation.
Norethisterone was provided to Group I patients. The dosage was 5 mg tablet, twice daily after food starting from the 5th day of menstrual cycle to the 25th day of the cycle.
Low-dose COC pill (containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel) was provided to Group II patients. The dosage was 1 tablet after food, at the bedtime, to take starting from the 5th day of menstrual cycle to the 25th day of the cycle.
Both of the drugs were supplied by the institution where the study was conducted.
Demographics of the patients were recorded during recruitment of the patients. Pretreatment PBAC score and hemoglobin level were recorded on the first follow-up visit appearing with PBAC score (i.e., before the group division). The PBAC on the 6th cycle after commencement of treatment was taken as the posttreatment PBAC score. Posttreatment hemoglobin level was tested after the 6th cycle. These data were stored for statistical analysis.
For the statistical analysis, α was set at 0.05. Categorical variables were expressed in numbers and percentage of patients and compared by Chi-square test. Continuous variables were expressed in mean and standard deviation. For comparison of pre- and posttreatment PBAC score and hemoglobin level, paired t-test was used. For comparison of improvement (posttreatment–pretreatment) in PBAC score and hemoglobin level, unpaired t-test was used. Statistical analysis was carried out in GraphPad Prism version 6.01 (GraphPad Software, La Jolla, CA, USA).
| Results|| |
A total of 50 patients with a mean age 28.62 ± 9.84 years (range: 13–45 years, confidence interval: 25.82–31.42) comprised the Group I (i.e., group which received norethisterone treatment) and a total of 50 patients with a mean age 28.42 ± 10.08 years (range: 15–45 years, confidence interval: 25.56–31.28) comprised the Group II (i.e., group which received low-dose COC pill treatment). Age range-wise distribution of patients with their demographics is shown in [Table 1].
|Table 1: Demographic details of the study patients in two intervention group|
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Pre- and posttreatment PBAC score and hemoglobin in Group I and Group II are shown in [Table 2]. There was a statistically significant improvement of PBAC score and hemoglobin after the treatment in both groups of patients.
|Table 2: Pretreatment and posttreatment pictorial blood assessment chart score and hemoglobin level|
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The improvements (posttreatment–pretreatment values) in PBAC score and hemoglobin level is shown in [Table 3]. There was no significant difference in Group I and Group II in terms of improvement in PBAC score and hemoglobin level.
|Table 3: Improvements (difference between posttreatment and pretreatment values) in PBAC score and hemoglobin in two intervention groups|
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Side effects of the drugs, as reported by the patients, are shown in [Table 4]. Nausea/vomiting was more experienced with low-dose COC (24% vs. 6%). In contrast, irregular menstrual bleeding (22% vs. 4%), weight gain (20% vs. 6%), and acne and hirsutism (12% vs. 0%) were higher with norethisterone treatment.
| Discussion|| |
In this study, first, we evaluated the efficacy of norethisterone in the improvement of blood loss in patients presenting with DUB. It was observed that norethisterone was able to reduce the PBAC score and increase the level of hemoglobin after treatment of 6 months [Table 2]. It has been reported that a significant number of Indian women suffer from DUB and it has several negative effects on physical, emotional, sexual, and professional life., Hence, an evidence-based first-line treatment is commonly provided by a general physician or family physicians. If the management fails, the physician may refer the patients to specialist doctor for further evaluation. A study conducted by Ashraf et al. reported that levonorgestrel-containing intrauterine device (IUD) is better than the oral norethisterone. However, IUD acceptance still faces challenges. In contrast, orally taken drugs are easy to take with less side effects. It is still obscure what causes DUB. However, a progesterone-related multiple morphological and functional endometrial changes are frequently seen in patients presenting with DUB. Moreover, maintaining a sustained level of progesterone helps in regaining near-normal level of menstrual bleeding. Finding of the current study supports the efficacy of norethisterone as a treatment mode in DUB.
In addition to the efficacy of norethisterone, this study also supports the use of low-dose COC pills in the improvement of blood loss associated with DUB [Table 2]. Previous studies established the efficacy of COC in the treatment of DUB.,, In contrast to norethisterone, COC pills contain both estrogen and progestogen. It is given for 3 weeks, and then, it is stopped for a week. In this pill-free week, women experience hormone withdrawal bleeding. It significantly reduces the menstrual blood flow rate. If otherwise not contraindicated, COC is widely accepted due to its once in a day dosing.
When the improvement level was compared between the norethisterone and low-dose COC pills, it was found that there was no difference between the efficacies of two methods [Table 3]. Hence, a clinician may decide anyone between these two methods. However, when the side effects were evaluated [Table 4], it was found that the most common side effect of norethisterone was irregular menstrual bleeding and most common side effect of low-dose COC was nausea/vomiting. Considering the patient reported side effects, low-dose COC stands at a better position than the norethisterone. When patients come with complaints of HMB, the presence of irregular bleeding during treatment may be a reason of lower acceptance. However, concluding on this issue was beyond the scope of the current study.
Limitations of the study
This study has several limitations. The subject of the study was recruited from a single tertiary care hospital. For diagnosis of HMB, PBAC score was used which is a semi-subjective method of assessment. As the score in PBAC was recorded by the patients, there may be error in evaluation of the amount of blood. Ovulatory and anovulatory DUB was not separately taken into consideration. Posttreatment evaluation was done after 6 months. Further follow-up was suggested to patients but not included in this study due to the limitation of time. The impact of treatment in the improvement of the quality of life was not assessed. Furthermore, pain score was not assessed in the study. These factors may be considered in future studies.
| Conclusion|| |
Both norethisterone and low-dose COC pills were found to be equally effective in reduction of blood loss in DUB. Considering the single dosage form and lower side effects, low-dose COC may be a better choice than norethisterone for the management of DUB. Further studies are needed to compare norethisterone and COC pills in compliance to treatment for a prolonged period.
We thank the participating patients and their family members for their cooperation in conduct of the study. We are thankful to the nursing staff and our colleagues of the Department of Gynecology and Obstetrics, Burdwan Medical College and Hospital, West Bengal, India, for their help and guidance during the study. We acknowledge the help of Mrs. Sarika Mondal, Freelance Medical Writer, ORCID: 0000-0001-5039-9919, for her help during the preparation of this manuscript.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4]