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 Table of Contents  
ORIGINAL ARTICLE
Year : 2022  |  Volume : 36  |  Issue : 2  |  Page : 78-82

Prospective clinical study to evaluate role of centchroman in regression of mastalgia in rural population


1 Department of General Surgery, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India
2 Department of Surgery, Uttar Pradesh University of Medical Sciences, Etawah, Uttar Pradesh, India
3 Department of Surgery, S. N. Medical College, Agra, India
4 Department of Urology, King George's Medical University, Lucknow, Uttar Pradesh, India

Date of Submission03-Sep-2021
Date of Decision05-Mar-2022
Date of Acceptance04-Aug-2022
Date of Web Publication16-Nov-2022

Correspondence Address:
Dr. Shashi Prakash Mishra
Department of General Surgery, Institute of Medical Sciences, Banaras Hindu University, Varanasi - 221 005, Uttar Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jms.jms_115_21

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  Abstract 


Background: Mastalgia in the reproductive age group is common among women. Treatment is not yet standardized for these conditions. The majority of treatments used for mastalgia is costly and have side effects. The aim of our study was to find the efficacy of centchroman for regression of mastalgia in a predominantly rural population, measured by the visual analog scale (VAS).
Materials and Methods: A total of 140 patients were randomized into two groups: Group 1 (n = 70) patients treated with centchroman and Group 2 (n = 70) patients treated with placebo for 12 weeks. The main outcomes are evaluated after one week to look for any intolerance, followed by repeated follow-ups at four, twelve, and twenty-four weeks to evaluate the treatment response using the VAS score and the side effects.
Results: The mean age of patients in Group 1 was 29.63 ± 9.67 years and 32.32 ± 9.74 years in Group 2. The baseline mean VAS score was 6.40 ± 1.65 and 5.83 ± 1.69, respectively. After 2, 4, 8, 12, and 24 weeks of follow-up, the mean VAS score was significantly decreased in patients treated with centchroman. On intragroup comparison, the mean VAS score was significantly decreased at baseline to 2, 4, 8, 12, and 24 weeks of follow-ups. In both the groups, gastritis and headache were comparable, and delayed menstruation was significantly more in patients treated with centchroman.
Conclusion: Centchroman has substantial efficacy, with a marginal effect on regression, of mastalgia in women of the reproductive age group, and it can be used as the first line of treatment.

Keywords: Centchroman, mastalgia, visual analog scale score


How to cite this article:
Mishra SP, Singh SP, Singh SP, Gupta V, Gupta P, Sharma AK, Kumar S, Agarwal M. Prospective clinical study to evaluate role of centchroman in regression of mastalgia in rural population. J Med Soc 2022;36:78-82

How to cite this URL:
Mishra SP, Singh SP, Singh SP, Gupta V, Gupta P, Sharma AK, Kumar S, Agarwal M. Prospective clinical study to evaluate role of centchroman in regression of mastalgia in rural population. J Med Soc [serial online] 2022 [cited 2022 Nov 28];36:78-82. Available from: https://www.jmedsoc.org/text.asp?2022/36/2/78/361278




  Introduction Top


Mastalgia is a very common complaint seen in the Western population with large numbers of females,[1],[2] but not so common in Asian females.[3] In the premenstrual phase, mastalgia is a fairly common symptom that is typically mild in severity; however, some of them report extreme pain intensity for a prolonged duration that affects the quality of life.[2],[4],[5],[6] Fifteen percent of women with symptoms require drug care, according to breast clinic experience.[7] The Cardiff mastalgia clinic contained three components: cyclical, noncyclical, and chestwall pain to propose a new classification to aid in decisionmaking.[8]

Mastalgia typically reflects the discomfort that arises in the breast tissue, in particular. Getting breast pain has a negative effect on a woman. It may be more usual as a unilateral or bilateral condition later on. Consequently, it is advised to contact health centers if women have breast pain since many of them are misdiagnosed with breast cancer. There are two distinct types of mastalgia, of which one is cyclical and the other is noncyclical mastalgia. Cyclic mastalgia, which occurs in the luteal phase of the menstrual cycle, is the most common form of mastalgia, in general. The signs of breast pain accompanied by tenderness and heaviness are present in patients.

Mastalgia is predominantly encountered by women due to characteristics such as menstrual irregularity, oral contraceptives, hormone therapy, psychotropic medications, psychosocial characteristics, and emotional stress that contribute to breast pain. It affects the personal and sexual life of women and is infamous due to its complex etiology, less treatment options, and far less active research; it presents major restrictions on treatment.

The majority of pharmacological agents used for fibroadenosis and mastalgia are expensive and have serious adverse effects, with danazol being the most common (antigonadotropin). Meta-analyses of bromocriptine, tamoxifen, evening primrose oil (EPO), and danazol for the treatment of mastalgia were released by Srivastava et al.[9] In randomized studies, other agents such as B6 and E vitamins, diuretics, gamolenic acid, nonsteroidal anti-inflammatory drugs (NSAIDs), and caffeine withdrawal have also been tested, but have not been shown to be exceptional.[10] Progesterone creams, tablets, and injectables are no longer recommended. Low doses of oral contraceptive pills and oral progestogen containing ethinyl estradiol were also confirmed to have beneficial effects.[11]

Ormeloxifene (centchroman), which is a selective estrogen receptor (ER) modulator, has potential as a weak ER agonist and a strong ER antagonist (SERA).

We have conducted this randomized controlled trial to find out the efficacy of centchroman on regression of mastalgia in a predominantly rural population of north India, measured by visual analog scale (VAS).


  Materials and Methods Top


The study included women of reproductive age, predominantly from rural north India, presenting to surgical outpatient between January 2016 and June 2017 with mastalgia. The study was performed after approval by the institute's Ethical Committee, and the reporting of this study was done in compliance with the CONSORT statement for reporting on randomized controlled trials. The study included patients having mastalgia with VAS score ≥3 persisting for more than 7 days per cycle, after taking written and informed consent. Patients with jaundice, hepatic impairment, polycystic ovarian diseases, uterine cervical hyperplasia, severe allergic states, family history of thrombosis or breast cancer, first six months of lactation and pregnancy or planning for pregnancy, and patients who were not giving consent were excluded from the study. The study included a total of 140 patients who were randomized into two groups using a block randomization technique. Group 1 (n = 70) patients were treated with centchroman (30 mg) and Group 2 (n = 70) patients were treated with placebo for 4 weeks a day, followed by 8 weeks of alternating days. A bilingual patient information sheet (in Hindi and English) was prepared with information on breast pain, available treatment options with possible adverse reactions, and data on centchroman. Before taking consent for inclusion in the study, this was given to the patient. Patients were eventually randomized to receive centchroman 30 mg daily or placebo for 4 weeks, followed by alternating days for 8 weeks.

Patients in both groups underwent breast ultrasounds to rule out the presence of any lump or nodularity, or any other disorder involving different treatment modalities (namely, surgical). To keep a daily record of the pain during the cycles and time of menstruation, patients were asked to maintain a “pain diary.”

Pain severity was scored according to the visual analog scale (VAS) ranging from 0 to 10 on clinical examination; zero indicated no pain and 10 indicated very serious pain. Patients also underwent an ultrasound pelvic scan before beginning care to rule out polycystic ovarian disease and cervical hyperplasia, which are contraindications for using centchroman.

After initiation of therapy, patients were evaluated for drug tolerance after one week and subsequently every 4 weeks until 12 weeks and then at 24 weeks, and the response to therapy was assessed by VAS. Treatment in both groups was performed for 12 weeks, and patients were reassessed for any recurrence after 12 weeks. During each visit, pain charts were reviewed and compliance with tablet count and self-reporting was taken into account. The results were based on a comprehensive assessment of the patient's condition as well as its adverse outcomes.

Statistical analysis was performed using SPSS (Statistical Package for the Social Sciences) software (version 23.0) for Windows (IBM Inc., Chicago, USA). For categorical variables, Chi-square test and Fisher's exact test were used. On comparing two groups of the mean, Student's t-test and Mann–Whitney U-test were used. For paired samples, Wilcoxon signed-rank test was applied; P < 0.05 is considered statistically significant.


  Results Top


A total of 140 patients with mastalgia were randomized into two groups of 70 patients each as mentioned earlier and were treated daily for 4 weeks, followed by alternate days for the next 8 weeks. In this study, most of the patients were in the age group of 26–35 years (50%), followed by the age group of <25 years (32.15%), and 17.85% of patients were in the age group of more than 35 years of age. The mean age of patients treated with centchroman was 29.63 ± 9.67 years and placebo group was 32.32 ± 9.74 years, which was comparable (P = 0.0.103). The demographic and clinical characteristic of patients is shown in [Table 1].
Table 1: Characteristics of patients (n=70)

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On comparing VAS scores, the baseline mean VAS score in centchroman group was 6.40 ± 1.65 and in the placebo group was 5.83 ± 1.69. Both groups were comparable at baseline (P = 0.060). After 2, 4, 8, 12, and 24 weeks of follow-up, the mean VAS score was significantly low in patients treated with centchroman compared to placebo (P < 0.001 at all follow-ups) [Table 2] and [Figure 1].
Table 2: Comparison of visual analog scale score between centchroman and placebo at different time intervals (n=70)

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Figure 1: Comparison of VAS Score between centchroman and placebo at different time intervals. VAS: visual analog scale

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[Table 3] demonstrates the comparison of the intragroup mean change in the VAS Score in both groups at different time intervals. The mean baseline VAS score was significantly changed to 2, 4, 8, 12, and 24 weeks of follow-up (P < 0.001 for all follow-ups) in the centchroman group. The mean VAS score was also significantly changed at baseline in the placebo group at 2, 4, 8, 12, and 24 weeks of follow-up (P < 0.001 at all follow-ups). Both groups had a substantial change in mean at different time intervals; however, in the centchroman group, the difference in percent change in the mean VAS score was high.
Table 3: Intragroup change in visual analog scale score at different time intervals (n=70)

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On comparing side effects, 2 (2.9%) patients had gastritis, 5 (7.1%) had delayed menstruation, and 1 (1.4%) patient had a headache in centchroman group [Table 4]. In the placebo group, 1 (1.4%) patient had gastritis, 3 (4.3%) patients had a headache, and none of the patients had delayed menstruation. In both groups, gastritis and headache were comparable (P = 0.559 and P = 0.310, respectively), and delayed menstruation was significantly more in patients treated with centchroman (P = 0.023).
Table 4: Side effects (n=70)

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  Discussion Top


Mastalgia is the most common presentation among women for breast-related ailments and is attributed to fear of malignancy and disruption of normal life due to pain.[12] A search has always been ongoing to find a safe drug with minimal side effects. Therefore, it is important to treat these conditions with appropriate drugs and to control them for a longer period. Several drugs, include tamoxifen, goserelin, danazol, bromocriptine, topical NSAIDs, oral contraceptives, vitamins, antioxidants, evening primrose oil, and fish oil. Precautions like a sports bra, a diet high in carbs and low in fat, a caffeine-free diet, assurance, and daily monitoring.

There is a debate on the option of fibroadenosis and mastalgia treatment due to different medication efficacy, side effects, and cost; the latest addition is centchroman. It was first developed by the Central Drug Research Institute, Lucknow, India, and was included in 1995 in the National Family Welfare Program. There are mild adverse effects on endocrine, hematological, liver, cardiovascular, central nervous, and lipid function.[13],[14],[15],[16] Just a few reviews on the use of centchroman for mastalgia, fibroadenosis, and fibroadenoma are included in the literature review. These findings suggested that centchroman is safe or better than other medications, due to its limited side effects and cost-effectiveness.

The majority of patients in our study (82%) were less than 35 years of age, and half of the patients were in the age range of 26–35 years, with an overall mean age of 31.63 ± 9.51 years. A corresponding Indian analysis by Rajswaroob et al.,[17] Kumar et al.,[18] and Bansal et al.[19] also found similar results.

In both groups, the baseline mean VAS score was comparable (P = 0.060). After 2, 4, 8, 12, and 24 weeks of follow-up, the VAS score was significantly low in patients treated with the centchroman group, compared to placebo at all intervals. The mean VAS score at baseline was significantly changed to 2, 4, 8, 12, and 24 weeks of follow-up (P < 0.001 for all follow-ups) in the centchroman group. In the placebo group, a significant change was also observed at different time intervals; however, the difference in percentage change of VAS in the centchroman group is high.

In India, very few research on the use of centchroman for benign breast diseases such as mastalgia have been reported. These findings have shown that centchroman is safe or better than other medications, regardless of its limited side effects and cost efficacy. In the mastalgia group, Dhar and Srivastava[20] reported a massive response, with a decrease in VAS scores from 10 to 3 in 90% of patients in the first week, and almost all patients were painless at the end of the month; centchroman (on alternating days) was given 30 mg for three months. Comparing the effectiveness of danazol and centchroman on mastalgia, Tejwani et al.[21] demonstrated significant pain relief with centchroman 30 mg daily for 12 weeks. In patients treated with centchroman 30 mg twice weekly for 3 months for mastalgia, Kumar et al.[18] showed a substantial downward trend over five visits. In patients diagnosed with mastalgia, Jain et al.[22] observed an identical drug response given daily for 3 months when comparing tamoxifen and centchroman. In patients treated with centchroman twice a week for 3 months, Bansal et al.[19] observed a substantial decrease in the mean pain score of up to 3 months and 3 months after discontinuation of treatment. In patients treated with centchroman twice a week for 3 months, Rathi et al.[23] registered a significant decrease in the mean pain score over successive visits. From this study, they concluded that centchroman is a safe and cost-effective drug with significant efficacy for mastalgia regression in women of the reproductive age group with minimal side effects. Good compliance can be related to a normal dosage for 1 month, and an alternate day for the next 2 months, where patients feel less opioid use physically and are not too worried with the adverse effects.

Our results are consistent with other available Indian studies in the medical literature. One of the previous studies had side effects of high frequency, particularly ovarian cyst development with centchroman. Although limited in number, available studies substantially support this drug as a treatment of choice for mastalgia.

Our research was conducted in a single center with a small sample size. In comparison to other drugs, however, multicenter randomized double-blind controlled trials with a greater sample size are needed for global acceptance.


  Conclusion Top


The findings of our research should indicate that centchroman has substantial efficacy with limited side effects on mastalgia regression in women in the reproductive age group. We recommend that it should be administered as a single regular dose of 30 mg for 1 month for better compliance, then an alternate day for the next 2 months, where patients mentally feel that they are using less medication, so they are not overly anxious about the adverse effects.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Ernster VL, Mason L, Goodson WH 3rd, Sickles EA, Sacks ST, Selvin S, et al. Effects of caffeine-free diet on benign breast disease: A randomized trial. Surgery 1982;91:263-7.  Back to cited text no. 1
    
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Ader DN, South-Paul J, Adera T, Deuster PA. Cyclical mastalgia: Prevalence and associated health and behavioral factors. J Psychosom Obstet Gynaecol 2001;22:71-6.  Back to cited text no. 2
    
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Goodwin PJ, Miller A, Del Giudice ME, Singer W, Connelly P, Ritchie JW. Elevated high-density lipoprotein cholesterol and dietary fat intake in women with cyclic mastopathy. Am J Obstet Gynecol 1998;179:430-7.  Back to cited text no. 3
    
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Ader DN, Browne MW. Prevalence and impact of cyclic mastalgia in a United States clinic-based sample. Am J Obstet Gynecol 1997;177:126-32.  Back to cited text no. 4
    
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Davies EL, Gateley CA, Miers M, Mansel RE. The long-term course of mastalgia. J R Soc Med 1998;91:462-4.  Back to cited text no. 5
    
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Holland PA, Gateley CA. Drug therapy of mastalgia. What are the options? Drugs 1994;48:709-16.  Back to cited text no. 7
    
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IARC Working Group on the Evaluation of Carcinogenic Risk to Humans. Pharmaceuticals. Lyon (FR): International Agency for Research on Cancer; 2012. (IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, No. 100A.) Combined Estrogen–Progestogen Contraceptives , 2012. Available from: https://www.ncbi.nlm.nih.gov/books/NBK304327/. [Last accessed on 2022 Jun 10].  Back to cited text no. 11
    
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Makker A, Tandon I, Goel MM, Singh M, Singh MM. Effect of ormeloxifene, a selective estrogen receptor modulator, on biomarkers of endometrial receptivity and pinopode development and its relation to fertility and infertility in Indian subjects. Fertil Steril 2009;91:2298-307.  Back to cited text no. 14
    
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Kamboj VP, Setty BS, Chandra H, Roy SK, Kar AB. Biological profile of Centchroman – A new post-coital contraceptive. Indian J Exp Biol 1977;15:1144-50.  Back to cited text no. 15
    
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Vaidya R, Joshi U, Meherji P, Rege N, Betrabet S, Joshi L, et al. Activity profile of Centchroman in healthy female volunteers. Indian J Exp Biol 1977;15:1173-6.  Back to cited text no. 16
    
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Bansal V, Bansal A, Bansal AK. Efficacy of SEVISTA (Ormeloxifene) in treatment of mastalgia and fibrocystic breast disease. Int J Reprod Contracept Obstet Gynecol 2015;4:1057-60.  Back to cited text no. 19
    
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21.
Tejwani PL, Srivastava A, Nerkar H, Dhar A, Hari S, Thulkar S, et al. Centchroman regresses mastalgia: A randomized comparison with danazol. Indian J Surg 2011;73:199-205.  Back to cited text no. 21
    
22.
Jain BK, Bansal A, Choudhary D, Garg PK, Mohanty D. Centchroman vs. tamoxifen for regression of mastalgia: A randomized controlled trial. Int J Surg 2015;15:11-6.  Back to cited text no. 22
    
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