|Year : 2014 | Volume
| Issue : 4 | Page : 225-231
Comparative study of low-dose oral contraceptive pill and ormeloxifene in the treatment of dysfunctional uterine bleeding
Debasmita Mandal, Sumit Parmanik, Sima Surana, Abhijit Hazra, Saroj Mandal, Tapan Kumar Maity
Department of Obstetrics and Gynecology, IPGMER and SSKM Hospital, Kolkata, West Bengal, India
|Date of Web Publication||16-Oct-2014|
Qr. No. C/11, SSKM Hospital Campus, 242, A.J.C. Bose Road, Kolkata - 700 020, West Bengal
Source of Support: None, Conflict of Interest: None
Background: Role of oral contraceptive pill (OCP) and ormeloxifene (ORM) in dysfunctional uterine bleeding (DUB) is still in an exploring level. Aim: The aim was to observe the improvement of the menstrual bleeding pattern in terms of the amount, regularity, and hemoglobin (Hb) status of the women. Setting: Study was conducted in the Department of Obstetrics and Gynecology of IPGMER and SSKM Hospital, Kolkata a tertiary care teaching hospital. Design: Prospective randomized study with patients having subjective complaints of menorrhagia. Materials and Methods: A total of 36 women was treated with ORM 60 mg and OCP containing 30 μg ethinyl estradiol and 150 μg desogestrel was given to 34 women. Pictorial blood loss assessment chart (PBAC) was applied to assess the amount of bleeding. Statistical Analysis Used: Data were compared using a t-test (paired and unpaired) and Mann-Whitney U-test for numerical variables and McNemar's Chi-square test for categorical variables. Results: The primary outcome showed a comparable PBAC score of ORM in first posttreatment cycle and significantly better in following two cycles (PBAC - postC1: 0.118, PBAC - postC2: 0.016, and PBAC - postC3: 0.04). Group receiving OCP was observed to have good cycle regularity in comparison to ORM (P = 0.006). Hb rise in both groups was almost similar, OCP group revealed an improvement in mean Hb concentration of 0.65 g%, whereas ORM showed a rise of 0.72 g%. Secondary outcomes were adverse reactions, satisfaction level, and poor responders in both groups. Conclusion: ORM is effective in treating DUB in almost in all aspects and can be considered as nonsteroidal option of therapy.
Keywords: Dysfunctional uterine bleeding, nonsteroidal option, oral contraceptive pill, ormeloxifene, pictorial blood loss assessment chart score
|How to cite this article:|
Mandal D, Parmanik S, Surana S, Hazra A, Mandal S, Maity TK. Comparative study of low-dose oral contraceptive pill and ormeloxifene in the treatment of dysfunctional uterine bleeding. Int J Health Allied Sci 2014;3:225-31
|How to cite this URL:|
Mandal D, Parmanik S, Surana S, Hazra A, Mandal S, Maity TK. Comparative study of low-dose oral contraceptive pill and ormeloxifene in the treatment of dysfunctional uterine bleeding. Int J Health Allied Sci [serial online] 2014 [cited 2020 Feb 21];3:225-31. Available from: http://www.ijhas.in/text.asp?2014/3/4/225/143056
| Introduction|| |
Dysfunctional uterine bleeding (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 reproductive age group. Though the predominant cause of DUB is prolonged estrogenic stimulation on the endometrium, recently attention has been focused on local endometrial factors such as imbalance of different components of endometrium prostaglandins, endometrial vasculopathy, or local coagulopathy. Moreover, defects of local endometrial receptors either estrogen or progesterone can cause an abnormal endometrial response to normal hormonal milieu. The traditional surgical treatment only treats the symptoms rather pathology. It has been estimated that two million women in the United States present annually with complaints of excessive uterine bleeding and that about 150,000 undergo hysterectomy, which accounts for 20-30% of all hysterectomies performed.  Globally, health care systems are focusing on low morbidity and low costs, therapeutic intervention. Hence, medical treatment for DUB is high on the priority list. Current medical therapy falls into two broad groups: Both nonhormonal and hormonal (prostaglandin synthesis inhibitors, antifibrinolytics and ethamsylate, progestins, oral contraceptive pills [OCPs], danazol, gestrinones, GnRH analogs, antiprogestins, etc.). Oral contraceptives have long been used clinically to decrease menstrual flow. ,, Although this effect was first demonstrated with oral contraceptive formulations that contained higher doses of both estrogens and progestins than the agents used today, low-dose combined oral contraceptives have been shown to have a similar effect.  Another category of the therapeutic agent that is ormeloxifene (ORM), anon steroidal, selective estrogen receptor modulator (SERM) and has been used for past 20 years as an oral contraceptive. , It is a good option for menorrhagia leading to 77-85% reduction in menstrual blood loss (MBL) and causes amenorrhea in 17-42% patients. , Here, we observed the effectiveness of low-dose OCPs and ORM in the treatment of DUB. It also proposed to compare the efficacy, acceptability, and adverse effects of the two drugs. Specific objectives of this study are: (1) To observe decrease in menstrual bleeding, (2) regularity of the menstrual cycle, and (3) improvement in hemoglobin (Hb) levels.
| Materials and methods|| |
The patient screening and recruitment were carried out at the gynecological outdoor and those admitted indoor in Department of Obstetrics and Gynecology of IPGMER and SSKM Hospital, Kolkata, which is a tertiary care teaching hospital. This was a prospective randomized study conducted between April 2010 and May 2011 with patients with subjective complaints of menorrhagia. The analysis was adhered to the declaration of Helsinki for Biomedical Research Involving Human subjects and study protocol was ethically permitted from IPGMER and SSKM Hospital Ethical Committee. About 98 patients with subjective complaints of menorrhagia were enrolled for the study, and those with objectively demonstrable menorrhagia (70 patients), were included in statistical analysis. Inclusion criteria for subjects included; women in age group of 18-50 who attended outpatient department (OPD) with subjective symptoms of excessive MBL irrespective of bilateral tubal ligation. Exclusion criteria comprised of: Any organic pelvic pathology, acute heavy bleeding, hemodynamically unstable patients, postmenopausal bleeding, recent history or clinical evidence of jaundice, renal disease, polycystic ovary syndrome, chronic cervicitis or cervical hyperplasia, chronic illness, for example, tuberculosis, past history or family history of thromboembolic diseases, known or suspected cancer of breast or other estrogen-dependent cancers, hypersensitivity to drugs. Women in age group of 18-50 years who attended OPD with subjective symptoms of excessive MBL were at first subjected to the detail history taking and physical examination. History included her chief complaints, duration of her symptoms, history of present illness, obstetric history, menstrual history, H/O past illness, surgical history, family history, H/O medication including contraceptives, personal history, and any significant relevant history. Then a thorough clinical examination was performed which included; general survey, systemic and gynecological exam with special emphasis on pelvic exam along with per speculum, per vagina, and bimanual exam to exclude any organic pelvic pathology. All women underwent ultrasonography assessment of pelvic organs to exclude any previously missed uterine or adnexal pathology such as pregnancy complications and uterine fibroid adnexal mass.
From the history and clinical examination, those with probable diagnosis of DUB were subjected to some investigation and objective assessment of MBL in two pretreatment baseline menstrual cycles.
In this study, objective assessment of MBL was done by following method as devised by Higham et al., pictorial blood loss assessment chart (PBAC). 
All patients were instructed to use a sanitary napkin of the same brand which have been shown to have similar absorbent capacities and scored depending upon the level of soiling and passage of clots as follows. PBAC score of a given cycle was obtained by adding scores depending on numbers of pads used, level of soiling, and number and size of clots passed.
After making the diagnosis of DUB from history, clinical examination, and investigations, patients were randomly divided into two groups:
- Group A: Patients in this group were treated with ORM 60 mg orally twice a week (wednesday and saturday) for total 12 weeks (n = 36)
- Group B: Patients in this group were treated with low-dose OCP containing 30 μg of ethinyl estradiol and 150 μg desogestrel from day 1 of the menstrual cycle to day 21 for 3 consecutive cycles (n = 34).
During the treatment period, each patient was followed-up monthly. Patient that did not follow strict follow-up protocol were excluded from the study. MBL was assessed during each period by PBAC. Various aspects of menstrual pattern and complaints associated DUB such as the amount of blood flow, duration, passage of clots, and dysmenorrhea were assessed during the follow-up period. Enquiry was made for any adverse effect of treatment during follow-up. Patient's improvement was assessed by performing blood Hb level after completion of therapy. Patient's level of satisfaction was judged with a well-designed questionnaire that is, general health, limitation of social activity sex life; wish to continue treatment with the same drug, to recommend this treatment modality to her relatives and friends with the same diagnosis.
Data were compared using a t-test (paired and unpaired) and Mann-Whitney U-test for numerical variables and McNemar's Chi-square test for categorical variables. A P < 0.05 was considered significant. Friedman's ANOVA followed by Dunn's posthoc test was used for multiple comparisons in PBAC scores. Software used were: Statistica version 6 (Tulsa, Oklahoma, USA: StatSoft Inc., 2001), MedCalc version 11.6 (Mariakerke, assessed Belgium: MedCalc Software 2001).
Among 98 DUB cases that attended hospital with the subjective complaint of excessive MBL, 25.51% (25 out of 98) revealed that menstrual blood loss is <80 ml/cycle (equivalent to PBAC score of <100) when assessed objectively. Three out of 73 (4.11%) patients did not complete the study as they violated the follow-up protocol. Ultimately, 70 patients completed the study (36 from ORM group and 34 from OCP group).
In the present study, of 70, 36 patients received treatment with ORM and 34 with low-dose OCP. Majority of study population (47.22%) in ORM group and 47.06% patients in OCP group are in the age group of 31-40 years. There was no significant age difference between two groups (P = 0.072). In this study, only 10% of DUB cases were nullipara and other were parous women and maximum cases comprised of the primipara to thirdpara.
| Results|| |
0In the present study, out of 70 patients 36 received treatment with ORM and 34 with OCP. Mean age of both groups of patients (38.22 years/ORM and 35.2 years/OCP) did not show any significant statistical difference. Majority cases with DUB were multiparous.
The mean PBAC score in pretreatment cycles were above 250 in both the groups. In subsequent cycles, during posttreatment course, there was effective improvement by both ORM and OCP [Table 1]. Two groups when compared to each other in terms of PBAC scoring, ORM significantly reduced the score in second and third cycles (129.3 ± 80.9 vs. 176.3 ± 91.5; P = 0.016 and 115.4 ± 65.6 vs. 156.9 ± 85.4; P = 0.40). Within the group, analysis showed a good reduction of PBAC score by each group in the posttreatment cycles (P < 0.001). The outcome measures at 3 months were shown in [Table 2]. The women receiving OCP had significantly controlled and regular menstrual cycle (P = 0.006), however, both groups did not show any huge difference in terms of improvement of Hb status and dysmenorrhea. Hb level ranged between 7.9-12.8 and 7.4-12.1 g% in the pretreatment phase and the 3 months follow-up revealed an improvement of Hb% between 8.4-13 and 8-12.7 g% in OCP and ORM group, respectively. Both these groups showed almost equal number of patient in highly satisfied, satisfied, and poorly satisfied categories [Table 3]. Adverse reactions of both drugs were shown in [Table 4]. Weight gain was more prominent with OCP treatment, but conclusion could not be drawn with such small sample. Evaluation of the poor responders revealed that the patients with submucosal fibroid polyp, secretory endometrium, and endometrial hyperplasia were refractory to treatment by both the drugs [Table 5].
| Discussion|| |
Wide varieties of treatment modalities are available for treating DUB, from medical therapy to minimally invasive surgery in the form of transcervical resection of the endometrium, thermal ablation and others to conventional hysterectomy. However, medical treatment should be the preferred modality of treatment when possible. Medical management of DUB is a challenging task with wide variations in the available drugs prescribed.
Objective assessment of menstrual blood loss
In the present study, we tried to evaluate the efficacy of two pharmacological agents in the treatment of DUB, namely ORM, an SERM and low-dose combined OCP. Of total study population, 25.51% of DUB patients seeking the gynecological advice with subjective complaints of heavy periods when assessed objectively for MBL, revealed no evidence of menorrhagia (blood loss <80 ml/cycle, equivalent to PBAC score of <100). Cameron et al. had also explained that with objective measurement of >50% of women complaining of heavy periods had MBL of <80 ml. 
Median pictorial blood loss assessment chart scores
In the present study, median PBAC score of ORM group during two pretreatment cycle was 261.5. The median posttreatment PBAC was 114. The median difference between baseline and posttreatment PBAC score was statistically significant. Biswas et al. in his study showed a significant reduction of median PBAC score from 272 in pretreatment cycles to 107.8 in posttreatment cycles that are statistically significant, correlating well with the present study. 
A pilot study by Kriplani et al. showed, pretreatment PBAC score at 388 and median PBAC was reduced to 80 (range 0-730) and 5 (range 0-310) after 42 women of menorrhagia treated with ORM for 4 months. 
In the present analysis, after comparison of the PBAC score between ORM and low-dose OCP, PBAC score of former drug was found to be statistically comparable in first posttreatment cycle and significantly better in following two posttreatment cycles when compared by Mann-Whitney U-test (P value for PBAC - postC1 is 0.059, P value for postC2 is 0.017, and P value for postC3 is 0.041). In spite of the extensive search, no comparative study between these two drugs is found for evaluating our result.
Presence of clots
The presence of clots is an obvious evidence of abnormal association with DUB. If it is present, it is almost invariably noticed and reported by the patient. Higham et al. reported that the presence of clots by a separate score is important in the assessment of DUB. 
In the present study, of 36 patents in ORM group, 33 reported the presence of clots in pretreatment cycles and after treatment only four patients reported occasional passage of clots showing an improvement in 80.6% of patients.
Similarly, Agrawal and Singh observed improvement of 80.43% cases by the absence of clots at the end of the therapy. 
Comparing efficacy of ORM and OCP to reduce the presence of clots, their effects were comparable and not statistically significant to each other (Chi-square test P = 0.202). No comparative study between these two drugs is found for evaluating our results.
Menstrual blood flow
Menstrual blood loss is such a personal experience of a woman that she, in most cases can very appreciably assess the loss and various complaints associated with it. Hence, patient's own assessment of control of bleeding and her improvement was given due weight age. In the present study, blood flow was reduced in 69.44% of patients and in 27.78% of patients it was much-reduced in patients given ORM.
In a trial carried out in India had shown 90.42% decrease in the blood loss. 
In OCP group, blood flow was reduced in 70.59% patients and much reduced in 27.78%. On the comparison between the two, it was not significant statistically (P = 0.6170). No such previous study is available for comparison with the present study.
One RCT (n = 45) was identified on women with menorrhagia comparing COCs with naproxen, mefenamic acid, and danazol. This comparative trial found that COCs reduced MBL by 43%. 
Duration of flow
In the present study, in ORM group, 61.11% patients (22 out of 36) reported decreased duration of menstrual flow. This disparity is due to the duration of menstrual flow being a subjective assessment; patients in our study probably ignored their scanty flow after being relieved from the heavy flow in contrast to their baseline cycles. In OCP group, 78.47% of patients had decreased duration of flow. Both the drugs were comparable in this respect (P = 0.110). No previous study is available for comparison.
In the present study, dysmenorrhea was improved in 76.67% patients (23 out of 30) in ORM group which well-correlated with the observation made by Biswas et al. showing an improvement in 78.26% of patients treated with ORM.  Hence, both the drugs were comparable in this respect (P =0.068) with ORM on a higher side.
In the present study, Hb level was measured before commencement of therapy and after completion of treatment. In ORM group, improvement in mean Hb level was 0.72 g/dl (Hb pre and post were 9.76 and 10.48 g/dl, respectively) and in OCP group was 0.65 g/dl (Hb pre and post were 9.79 and 10.44 g/dl respectively). Biswas et al. demonstrated a significant increase in mean Hb concentration of 1.31 g/dl in patients treated with ORM.  In another analysis, there was a significant increase in mean Hb concentration of 1.82 g% after 6 months.  Especially, the mean rise in Hb level was more with these studies. This may be due to prolonged treatment with ORM (at least 24 weeks) in contrast to 12 weeks in our study. Rise of Hb level between ORM and OCP groups when compared, no significant difference was seen (P = 0.876). Results of the present study could not be compared with others due to unavailability of such previous study.
In OCP group, cycle regularity was achieved in 90% of patients in this study. Group receiving ORM rather had scanty flow and ultimately amenorrhea.
In our study, amenorrhea following treatment was seen in 8.33% of patients (3 out of 36). Biswas et al. reported posttreatment amenorrhea in 17.45% of patients given ORM for DUB.  This difference from our study is probably due to prolonged treatment with ORM (24 weeks) in this study. Kriplani et al. reported amenorrhea in 42.9% patients in their study. 
Level of satisfaction and acceptability of treatment
Patient satisfaction with menstrual flow is highly subjective and dependent upon the relative decrease in flow, the absolute level, and personal perception of what constitutes "normal". Apart from that other factors like decrease in duration of flow, improvement in symptoms due to dysmenorrhea, and adverse effects of the drug also have a significant impact on patient's own assessment. Same adverse effect of the drug may have a different impact on different patients. Posttreatment amenorrhea is an example of such adverse effect. It is a welcome sign for a woman of perimenopausal age group, but it may not be acceptable to a woman of younger age group. In this study, 11.11% of patients in ORM group and 14.71% of patients in OCP group were poorly satisfied. No major side effects were noted in any of the treatment groups. Patient's compliance was also good in both the treatment groups.
No statistically significant difference was noted between two treatment groups (Chi-square test P = 0.867). No previous study is available for evaluating the result of the present one. In the present study, incidence of hysterectomy in poor responders in ORM group is 5.56% and in OCP group it is 11.76%. In another study by Biswas et al., only 8.2% women needed hysterectomy when treated with ORM.  Kriplani et al. observed, 21% of the patients underwent hysterectomy during a 10 months study period. 
Limitations of the study
It is a small sample size and short duration study with the absence of double blinded placebo controlled trial to control information bias. There was failure to allocate the subjects evenly in two treatment groups of different age composition. Large RCT are needed to compare the efficacy of these drugs with other medical therapies such as progestins, tranexemic acid, levonorgestrel-releasing intrauterine system. Long-term follow-up is required to observe the efficacy of these drugs and to note the recurrence of symptomatology.
| Conclusion|| |
Ormeloxifene is efficacious in the management of DUB. Apart from its efficacy, it has shown its superiority by good compliance due to convenient dose schedule and cost benefit for total therapy. Thus, ORM may be considered for the medical management of idiopathic menorrhagia, especially for patients who prefer the nonsteroidal treatment, that is, perimenopausal women, adolescents and those women who wish to preserve their fertility.
| Acknowledgment|| |
We acknowledge to our patients who have given their consent for this study.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]