Evaluating the Effect of Ormeloxifene on Multiple Fibroadenomas and Mastalgia.

INTRODUCTION: Most common benign breast conditions presenting in the breast clinics include fibroadenomas and mastalgia, both these conditions cause considerable anxiety in the patients. Among other treatment modalities, the hormonal drug treatments are gaining popularity. Ormeloxifene (centchroman) is an antiestrogenic drug which is shown to have effect in reducing the pain in mastalgia patients and the size of fibroadenoma.
OBJECTIVES: Ormeloxifene is selective antiestrogen and a nonsteroidal drug. It has a discerning antiestrogen action and hence is useful for the treatment of mastalgia and multiple small fibroadenomas. Hence, the objective of our study was to assess the effect of Ormeloxifene (centchroman) on multiple fibroadenoma and mastalgia.
MATERIALS AND METHODS: Patients with benign breast disease attending our surgery outpatient department from June 2016 to July 2017. Patients were started on Ormeloxifene 30 mg on alternate days for a period of 3 months. Patients were followed up to 6 months after the inception of the study. Parameters recorded include the Visual Analog Scale (VAS) for pain and ultrasonography for breast lump size.
RESULTS: Thirty patients were included in the study. We found very good response in the mastalgia; the VAS scores in these patients dropped from 10 to 3 in 90% in the 1st week of introduction of the drug, and at the end of 1 month, almost all of the patients were painless. Overall final response was noted in terms of complete dissolution and change in the size was noted in 34% partial response in 46 %, no changes in 17 % and increase in size of fibroadenoma was noted in only one case.
CONCLUSION: Novex is proved to be safe drug for the treatment of mastalgia and fibroadenoma. Its results were great in mastalgia group. At the end of 6 months, the number of surgeries (if needed) decrease and there is considerable improvement in the patient satisfaction rate. Copyright:

INTRODUCTION

Pain and lump are the common complains in the breast clinic. Almost 90% of these cases turn out to be benign,[1] but they are major cause of fear of malignancy.

The most common benign breast masses in adolescents include fibroadenomas, they are mostly found in patients under 30 years of age and appear as a single mass but in about 20% of the cases there may be multiple mass in one breast.[2] Women with multiple fibroadenomas mostly have familial history.[3] The exact etiology of multiple fibroadenomas is not known it is believed that the possible etiology may include the use of oral contraceptive pills (OCP's), estrogen and prolactin level disproportion in the body, local breast tissue reaction to estrogen, and dietary or inherited predisposition.[23]

Multiple fibroadenoma is defined by the unilateral or bilateral existence of at least three fibroadenomas in one breast of women of child bearing age.[2] Surgical treatment is usually required for symptomatic, more than 4cm size rapidly, enlarging, and the ones causing cosmetic breast deformity.[4] The management and treatment of multiple fibroadenomas can be challenging due to the rare occurrence and scarcity of original research on these conditions. It is observed that the surgical therapies are frequently discussed as the first-line of therapy for a breast mass. Multiple incisions or extensive surgeries required due to multiple lesions results in scarring,breast deformity and ductal damage along with psychological stress.[45] Management of multiple fibroadenoma should be aimed at reduction in size and growth of lesion with safe and acceptable cosmetic outcome so as to avoids psychological stress of pain and scar especially in younger patients.[4] Hence minimal invasive surgical procedures like vacuum-assisted breast biopsy and radiofrequency ablation are being preferred but are very expensive.[5] These days hormonal therapy has been attempted to subdue the growth of fibroadenoma. This involve antiestrogenic drug as it is considered that fibroadenomas arise from the hyperresponsiveness of the lobular tissue to estrogen.[6]

Selective estrogen receptor modulators (SERMs), such as Tamoxifen and Ormeloxifene are nonhormonal antiestrogenic drugs. Ormeloxifene (centchroman) has strong antagonist (on breast ductolobular epithelium) and weak agonist (on endometrium) action. In India, this drug has been available since 1990s as birth control pill and is marketed under the trade name Saheli.[7] The safety profile of this drug is outstanding with limited side effects as compared to tamoxifen, the side effects of which comprises of headache, nausea, weight gain, deferred, or protracted menstrual period.[8]

Mastalgia is breast pain which may be cyclical and non-cyclical exacerbation of pain depending on its relation with menstrual cycle.. It can cause interference in the daily life of females and it also raises fear and anxiety of breast carcinoma in them. Mastalgia is hormone dependant so when Estrogen and progesterone levels fall just before menstruation there is in reduction of cellular proliferation in the early follicular phase, leading to respite in pain and engorgement.[7] Agents bringing hormonal management such as Tamoxifen, Danazol, Bromocriptine, and LH-RH analogue are the choice of drug therapy for mastalgia. There is extensive research going on in this field to find a nonhormonal substitute and one such drug is Ormeloxifene (Centchroman).

The aim of this study is to observe the effect of ormeloxifene for the treatment of mastalgia and multiple fibroadenomas.

MATERIALS AND METHODS

This study was conducted on patients aged ≤35 years with fibroadenoma or mastalgia coming to the breast clinic were included in the study[5]. Patients with polycystic ovarian disease and fibroadenoma ≥5 cm were excluded from the study.

After taking written consent, to participate in the study, detailed history, demographic profiles and clinical features were recorded and were prescribed Centchroman 30 mg alternate day for 12 week. Patients were followed at 3 and 6 months to assess response to therapy. The results were formulated according to clinical examination, Visual Analog Scale (VAS) for pain, and ultrasonography for breast lump size.

The size of the lump was measured in volume, by breast ultrasound formula used for volume in cubic centimeter is (a × b × c × 0.52),

Whereas a = Largest dimension, b = Dimension at right angle to a, c = abs/2.

Statistics

The results were analyzed statistically with the help of mean and SD, percentage and paired t-test, where P < 0.05 was considered significant.[8]

RESULTS

This study included 30 patients with multiple fibroadenoma (≥03). In 20% cases (n = 06), positive family history was found with maximum no of cases in 21–25 years [Table 1].[910] History of oral contraceptives consumption was present in 23.3%. Increased incidence was found in the body mass index (BMI) group of 19–21 kg/m2 with an average BMI 19.5 kg/m2 [Table 1].

Table 1

The distribution of participants in experimental and control group

Age group in years	n (%)	BMI (range) weight/height2=kg/m2	Family history	History of oral contraceptives
<20	8 (26.6)	18-19	1	0
21-25	11 (36.6)	19-21	3	2
26-30	9 (30)	20-21	2	1
30-35	2 (6.6)	21	0	0
Total, n (%)	30 (100)	Average BMI=19.8	6/30 (20%)	3/30 (10%)

BMI: Body mass index

Right side predilection was found to be higher. Number of fibroadenoma is varied from 3-7 in each breast and is size of fibroadenoma ranged from 0.5 to 3 cm in Table 2.

Table 2

Initial side and size of the lesion

	Unilateral	Bilateral	Right side	Left side	Number of fibroadenoma in each breast
					3-4	5-6	≥7
n (%)	25 (83)	5 (16.6)	18 (60)	12 (40)	23 (76.6)	6 (20)	1 (3.3)

Twenty-three (80%) patients complained of severe pain with a VAS score of 10 and 7 patients (20%) were found to lie between 7 and 10 of VAS score. We found very good response in the mastalgia; the VAS scores in these patients dropped from 10 to 3 in 90% in the 1st week of introduction of the drug, and at the end of 1 month, almost all of the patients were painless.

Response of ormeloxifene therapy was evaluated at the end of 3rd and 6th month and was recorded in terms of reduction in size or complete disappearance clinically and by ultrasonography [Figure 1 and 2] [Table 3].

Figure 1

(a) Sonographic appearance of multiple fibroadenoma in left breast at 11 O'clock position of sizes 2.56 x1.08. (b) Follow-up sonographyof the same patient after Ormeloxifene given for 3 months showing complete response after 6 months, size 0.09x0.29

Figure 2

(a) Sonographic appearance of multiple fibroadenoma in right breast at 10 O'clock position of sizes 2.28 x 0.98 cm. (b) Follow-up sonographyof the same patient after Ormeloxifene given for 3 months showing partial response after 6 months, size 1.02x0.96 cm

Table 3

Shows lesion size at different time interval (by radiological evaluation)

Volume	Disappear, n (%)	<1 cm3, n (%)	1-2 cm3, n (%)	2-3 cm3, n (%)
At beginning of treatment	0	4 (13.3)	10 (33.3)	16 (53.3)
At the end of 3rd month	1 (3.3)	3 (10)	12 (40)	14 (46.6)
At the end of 6th month	9 (30)	7 (23.3)	6 (20)	8 (26.6)

Overall, final response was noted in terms of complete dissolution and change in the size is 34% partial response in 46 %, no changes in 17 % and increase in size of fibroadenoma was noted in only one case Table 4.

Table 4

Distribution of response in size of fibroadenoma to ormeloxifene (by clinical and radiological evaluation)

Response	At the end of 3rd month, n (%)	At the end of 6th month, n (%)	Overall result, n (%)
Complete dissolution/response	1 (3.3)	9 (30)	10 (34)
Partial response (50% decrease in size clinically and by USG)	4 (13.3)	10 (33.3)	14 (46)
No response	2 (6.6)	3 (10)	5 (17)
Increased in size	0	1 (3.3)	1 (3)

USG: Ultrasonography

DISCUSSION

Multiple fibroadenoma is a rare benign disease so natural history and etiopathogenesis is poorly understood. Although unknown,the possible hormonal aetiology may be hypersensitivity of breast tissue to oestrogen by risk factors such as oral contraceptive pills, dietary factors and hereditary predisposition.[23] Usually in multiple fibroadenoma, average number of masses in a single breast is 3-5 but more numbers have been reported in various studies including this study.[3] Increased body mass index and oral contraceptives could not be established as a risk factor in this study as in other studies.[4] A strong family history was found associated with multiple fibroadenoma in many studies and in this study it was found in 20% of cases.[8]

Mastalgia can cause interference in the daily life of females, and it also raises fear and anxiety of breast carcinoma in them. There are many drugs available for the cure of mastalgia, which include bromocriptine, danazol, Tamoxifen, diuretics, and topical Nonsteroidal anti-inflammatory drugs gels with varying side effects and efficacy.[910]

In a study conducted by Bhupendra sharma, it was observed that the VAS scores in mastalgia patients were reduced to less than or equal to 3.[11] There results are in unison with our study. Ormeloxifene is a novel non-steroidal, selective antiestrogen(SERM)which has been used for the treatment of mastalgia and multiple small fibroadenomas. It is relatively free from adverse effects such as vomiting, nausea, dizziness, and weight gain. It does not interfere with ovulation, and hence, there is no delay in return of fertility after stopping the drug. He only adverse effect observed is delayed menses in <10% of cycles.[12]

Centchroman does not have any side effects on endocrine system, liver and lipid function, and no serious complications such as heart attack, stroke, or thrombosis are associated with it.[1011]

Our results of ormeloxifene on multiple fibroadenoma showing complete dissolution in 34% partial response in 46 % and no response in 17% This is consistent with that of Dhar et al, Tejwani et al and Gupta et al who studied the effect of Ormeloxifene in the management of mastalgia and fibroadenoma.[121314]

CONCLUSION

Nonsurgical management is preferred in management of multiple fibroadenoma of breast because of multiple and benign nature of the lesions. Ormeloxifene has been found to be a suitable alternative to surgical option in management of multiple fibroadenoma and mastalgia patients thus reducing the risk of surgery, anaesthesia, cosmesis and damage to lactiferous glands. It is of utmost importance that we tailor the management of benign conditions such as mastalgia and multiple fibroadenoma to the needs of the patient. It is observed that Ormexifen is an effective drug in reducing the pain in the patients of mastalgia and is also effective regression of fibroadenoma.

Limitations of the study

The duration of the study is 1 year, and the data presented here are based on the 6 months' follow-up. Long-term results of ormeloxifene require further studies in future.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.