Role of Centchroman in Regression of Mastalgia and Fibroadenoma
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- Dhar, A. & Srivastava, A. World J Surg (2007) 31: 1180. doi:10.1007/s00268-007-9040-4
Centchroman (Ormeloxifene) is a novel non-steroidal, selective antiestrogen. Because of its selective antiestrogen action, centchroman has been used for treatment of mastalgia and fibroadenoma.
Materials and Methods
Benign breast disease patients up to 35 years of age attending our surgery outpatient department from August 2003 to September 2004 and fulfilling the inclusion criterion were included in this study. They were started on centchroman 30 mg on alternate days for a period of 3 months and were followed up for 6 months. Results were recorded as per clinical examination, visual analog scale (VAS) for pain, and ultrasonography for breast lump size.
A total of 60 patients were included in this pilot study, 42 (70%) of whom had mastalgia with or without nodularity, and 18 (30%) had fibroadenoma. Noncyclical pain was recorded in 38 patients (90%), and cyclical pain was recorded in only 4 (10%) patients. A VAS score of 10 was recorded by 33 (80%) patients (severe pain), and the remaining 9 patients (20%) had VAS scores from 7 to 10. Fibroadenoma size ranged from 1.5 to 5 cm., single or multiple in one or both breasts. There was a good response in the mastalgia group, with a decrease in the VAS scoring from 10 to 3 in 90 % of the patients in the first week. Almost all of the patients were painless at the end of one month, with complete disappearance of the nodularity. In the fibroadenoma group there was a mixed response, with complete disappearence in 40%, partial regression in 20%, and no response at all in the remaining 40%. There were very few side effects.
Centchroman is a safe nonsteroidal drug for the treatment of mastalgia and fibroadenoma. It has shown good results in mastalgia and is a safe drug as compared to the drugs of choice used at present (danazole and bromocriptine). Further randomized studies are in progress and are needed to determine its definitive role in this patient group.
Benign breast disease especially mastalgia is a challenge to treat. Like the cause of mastalgia, the treatment also has always been a reason for the research. Different drugs have been used with varied responses. The most commonly prescribed nonsteroidal drug, evening primrose oil, has been found to have no benefits over placebo . Other drugs used at present are danazol, bromocriptine, tamoxifen, and LHRH analog. Most of them are steroid-based drugs with significant side effects.
Centchroman is a novel nonsteroidal, selective antiestrogen synthesized by the Central Drug Research Institute, Lucknow, India. It was included in the National Family Welfare Programme in 1995. It is an oral contraceptive and has the advantage of less frequent administration. In lactating women, it is excreted in milk in quantities considered unlikely to have any deleterious effect on suckling babies. It is free from side effects commonly associated with steroidal oral contraceptives like nausea, vomiting, weight gain, and dizziness. It does not delay return of fertility. It maintains normal ovulatory cycles because the low dose and two to three times a week administration schedule minimizes any effect on the hypothalamic–pituitary–ovarian axis. It has no side effects except that it may prolong the menstrual period duration in about 10% of the cycles and in a few cases of polycystic ovarian disease.
Because of the advantages of this drug as a nonsteroidal antiestrogen with almost no side effects, it was used in the treatment of the benign breast diseases mastalgia and fibroadenoma. A pilot study was conducted before the randomized trial. The details of the pilot study are given below; the randomized clinical study is ongoing. The use of this drug for mastalgia and fibroadenoma has been permitted by the drug controller of India and the ethics committee of our institute.
The primary objective of this study was control of mastalgia by centchroman, measured by visual analog scale. To accomplish that goal, we conducted this study of the role of centchroman in regression of fibroadenoma measured by ultrasound examination.
Materials and methods
This study was conducted between August 2003 and September 2004 in the Surgery Out Patient Department at All India Institute of Medical Sciences. All the patients coming with a history of benign breast disease up to 35 years of age were evaluated for this study. Patients with a history of mastalgia with or without breast nodularity and cases of fibroadenoma of less than 5 cm size, after triple assessment, were included in this study. Triple assessment included clinical examination, imaging, and pathological examination. All patients had clinical examination and ultrasound of the breasts. The size of the breast lump was recorded. Fine-needle aspiration cytology was done in fibroadenomas and the dominant nodule in patients with nodularity of the breast. All sexually active women were sent for a detailed gynecological examination, as well as ultrasound of the pelvis to rule out polycystic ovarian disease.
The medical history and examination were recorded pro forma. Pain score was recorded on a visual analog scale (VAS) from 0 to 10. Those having mild pain were not included in this study; instead, they were given reassurance and scheduled for follow-up. Patients having polycystic ovarian disease, cervical hyperplasia, or pregnancy, and those wishing to conceive in the near future were not included in the study.
The main outcome of interest in the mastalgia group was relief of breast pain as measured on the VAS of 0–10. Secondary outcome measures were (1) change in nodularity, which was recorded by palpation of the breast and coded as complete or partial remission at 1, 2, 4, 8, 12, and 24 weeks; (2) relief of breast tenderness, assessed by palpation and coded as absence or presence.
The outcome in the fibroadenoma group was decrease in size of the lump measured clinically and with the help of ultrasound at the beginning, at the end of 3 months, and again at 6 months.
This study was conducted on a total of 60 patients whose age ranged from 17 to 35 years, with a mean of 26 years (4 SD). The largest number of patients, 40 (68%), were between 21 and 30 years of age. Patients presenting to the outpatient department with breast pain numbered 42 (70%); those with a breast lump numbered 18 (30%). Breast pain was unilateral in 21patients (50%) and bilateral in 21(50%). Cyclical pain was observed in 8 patients (19%) and noncyclical breast pain in 34(81%).
Presence of mastalgia
Nodularity and tenderness
There were two side effects observed. One patient had an allergic rash in response to the drug, after the second dose. The second side effect was a delay in menstruation of 7–10 days in 3 patients. Two patients had complete amenorrhoea during the treatment period only. They returned to normal cycle at 6 months follow- up. In both cases, a pregnancy test was negative.
Mastalgia is one of the commonest symptoms in patients attending a breast clinic and is also the most frequent reason for breast-related consultation in general medical practice . A duration of painful nodularity of more than one week of the cycle is a useful definition for differentiation from normal discomfort, and the severity of the pain can be quantified with a VAS chart. It is broadly categorized into cyclical and non-cyclical mastalgia . The most common type of discomfort is related to the menstrual cycle, and particularly to ovulation. Two or 3 days of premenstrual breast tenderness or heaviness every month should be regarded as temporary/normal. Fine nodularity of the breast that begins a short time before menstruation and regresses postmenstrually is also normal. Duration of symptoms of more than 1 week per cycle is taken as significant and can be termed “pronounced.” Again, severity is documented using the VAS chart. Bilateral pain and nodularity are also common. The pain often radiates to the axilla and down the medial aspect of the upper arm, presumably as a referred pain via the intercostobrachial nerve.
Noncyclical mastalgia lacks any relationship with events of the menstrual cycle. It falls into two groups: true non-cyclical mastalgia and musculoskeletal pain. True non-cyclical mastalgia occurs in both premenopausal and postmenopausal women. The non-cyclical pattern differs in several respects from the cyclical form. The pain tends to be well localized in the breast and is more frequently subareolar or in upper outer quadrant. It is scored by the patients at a lower intensity than the cyclical pattern. Nodularity is less prominent than in the cyclical group, but it is reported by 54% of the patients. When differentiated from musculoskeletal pain, non-cyclical breast pain has a better response to hormonal therapy than previously thought .
Musculoskeletal pain is almost always unilateral (92%) and falls into two groups: Tietze’s syndrome and lateral chest wall pain. In Tietze’s syndrome, typically the pain is felt within the medial quadrants of the breast and tenderness occurs on pressure over the affected costochondral junction.
Edema due to water retention has been suggested and discarded as a cause of mastalgia . Three hormonal theories emerged regarding the etiology of painful nodular breasts: increased estrogen secretion from the ovary, deficient progesterone production (“relative hyperoestrogenism”)  and hyperprolactinemia. Early studies failed to support the first two theories, as hormone levels were found to be no different in patients and controls[7–9]. One further study of daily sampling of prolactin at a fixed time throughout the menstrual cycle revealed a small but statistically significant difference between women with cyclic pain and controls . Peters and colleagues examined the stimulated prolactin response to thyrotropin-releasing. hormone (TRH) in a mixed group of benign disease patients and found that those with mastalgia had a significantly greater rise in prolactin compared with controls. The basal prolactin levels were not significantly different between the groups. These studies strongly suggest that there is a disturbance of hypothalamic control in women with cyclical mastalgia [11, 12].
There seems to be a definite role of estrogen receptor (ER) in the pathogenesis of benign breast diseases. In a study to estimate the value of ER, it was found that the patients with ER-positive breast disease responded better to danazol than patients with ER-negative breast disease .
Another hypothesis proposes an abnormality of prostaglandin synthesis secondary to deficient essential fatty acid (EFA) intake in the diet of affected women . Measurement of plasma fatty acid  has confirmed abnormal profiles in patients with mastalgia, as increased saturated fatty acids, and EFA reduced. The end result of EFA deficiency accentuates prolactin effects on breast cells because of deficient production of prostaglandin E1. Elevation of HDL-C (high density lipoprotein-C) has been reported in patients with cyclical mastalgia but not in those with non-cyclical pain .
Reassurance: The most successful treatment is reassurance that a patient’s symptoms are not due to cancer. A Brazilian study verified an overall success rate of 70.2% with reassurance in a study of 85 patients with mastalgia. Reassurance was effective in 85.7% of the patients with a mild form of mastalgia, in 70.8% with a moderate form, and in 52.3% with a severe form . Active breast movement on the weak suspensory ligaments may contribute considerably to mastalgia. Good external support by a sports bra can relieve most of the symptoms .
Oral contraceptives: OCP have been shown to have protective effect in benign breast disorders .
Diuretics: There is no rational basis for the use of diuretics in the treatment of breast pain, as demonstrated by the lack of correlation between retention of body water and symptoms .
Topical application of NSAIDs: Tropical use of NSAIDs has been found to be effective in mild type of mastalgia .
Evening primrose oil: The fatty acid deficiency hypothesis has led to the testing of treatment by supplementing the diet with an EFA. The oil of evening primrose (EPO), which is unique in containing 7% linolenic acid and 72% linoleic acid, represents the richest natural source of EFAs known. Several trials have shown EPO to be useful in treating mild and moderate cases of cyclical mastalgia . Its effect has been shown in a randomized double-blind clinical trial in which 120 premenopausal women with severe chronic mastalgia were placed randomly into four groups for 6 months: (1) fish oil and control oil, (2) evening primrose oil and control oil, (3) fish oil and evening primrose oil, or (4) both control oils. Corn oil and corn oil with wheat germ oil were used as control oils. The decrease in days with pain was 12.3 % for evening primrose oil and 13.8% for its control oil; the decrease in days with pain was 15.5% for fish oil and 10.6% for its control oil. Neither evening primrose oil nor fish oil offered clear benefit over control oils in the treatment of mastalgia .
Gamolenic acid (GLA): An essential polysaturated fatty acid (PUFA) is present in large quantities in evening primrose oil. Low levels of the metabolites of GLA have been identified in plasma of women with cyclical mastalgia . Addition of antioxidants to PUFA may enhance clinical response because PUFA are thought to be denatured by oxidation in the body. A study from Cardiff University in 2005, published results after randomizing patients with mastalgia into four groups at multiple centers (1) GLA and antioxidants, (2) placebo fatty acid and antioxidants, (3) GLA and placebo antioxidants, and (4) placebo fatty acids. The investigators concluded that GLA efficacy did not differ from placebo, regardless of whether antioxidant vitamins were present.
Danazol: The action of danazol in humans is not clearly defined, because it only interferes with follicle stimulating hormone and luteinising hormone at high doses. The hormonal effects of danazol treatment is a low luteal progesterone level (suggesting anovulation) [27, 28]. The side effects are mainly amenorrhea, the incidence of which increases with dose, and various mild androgenic effects such as weight gain, acne, and hirsutism. Current practice in India is to start treatment at 50 mg once daily and then increase to 50 mg twice daily if the response is not complete. The maintenance dose should be given for at least 3 months. In the West, the recommendation is to use a maintenance dose of 100 mg daily on alternate days [29, 30]. Danazol appears to be the best agent for severe breast pain and nodularity, with an overall improvement rate of 70%. It is superior to bromocriptine in the treatment of cyclical breast pain .
Bromocriptine: The cyclical pattern of pain is significantly reduced by bromocriptine, when compared with placebo . It is a prolactin-lowering agent that blocks the release of prolactin from the pituitary by dopaminergic receptor stimulation. The results of the Cardiff study have been confirmed by other controlled trials [33–36]. The problem with bromocriptine is that some women experience severe side effects, the commonest being nausea, vomiting, and dizziness. The severity of side effects can be reduced by increasing the drug doses slowly and avoiding doses higher than 2.5 mg twice daily.
Tamoxifen: In a double-blind study, tamoxifen, 10 mg daily, significantly improved mastalgia with response rates of 98% for cyclical and 56% for non-cyclical pain. Side effects were reported to be “minimal” . Extending treatment beyond 3 months did not increase response rate, nor did it reduce the relapse rate. On the basis of present experience, the appropriate dose is 10 mg daily for 3 months, repeated for relapse if necessary, with further courses given only after full consideration of the possible long-term side effects.
LHRH analog: Use of goserelin (LHRH analog) was studied in a large randomized multicenter study in the management of mastalgia. It is an effective short-term treatment; however, because side effects are common, it is reserved for patients whose pain is refractory to other treatment modalities .
Surgery: When medical measures fail, surgery option may be the only remaining option. Mammoplasty may relieve mastalgia in large pendulous breasts. Subcutaneous mastectomy should be the last resort, only undertaken after all drug therapies fail to cure severe mastalgia. The patient should be reviewed by a psychologist prior to surgery.
Fibroadenomas are the most common breast masses in women younger than 30 years of age and the most common solid masses in breasts of woman of all ages, with a peak incidence at around 20 years of age . The usual practice is to excise the fibroadenoma or leave it to its natural course. Fibroadenoma has a chance of spontaneous natural regression of about 30% over a period of years. Dent and Cant reported complete disappearance of fibroadenoma naturally in 31%, a decrease in size in 12%, remained static in 25%, and increased in 32% over a period of 24 months without treatment .
Hormonal treatment of fibroadenomas has been suggested by some studies. Viviani et al.  evaluated the ultrasonographic volume of fibroadenomas in 62 premenopausal women treated with tamoxifen at the doses of 5, 10, 20 mg/day or with placebo for 50 days. They concluded that tamoxifen reduced fibroadenoma volume significantly (by around 20%) when administered for 50 days at the dose of 20 mg/day. Further clinical studies are suggested using the drug for a longer period of time.
Centroman as an alternative treatment
In an effort to better treat mastalgia and fibroadenomas, we tried centchroman, a novel nonsteroidal chemical that is marketed in India and that could be a choice of the future.
Centchroman elicits weak estrogen agonistic and potent antagonistic activities but is devoid of progestational, androgenic, and anti-androgenic activities [42–46]. There is an early return of fertility after stopping this drug; therefore it is safe in the treatment of unmarried women and those who wish to conceive after treatment. No teratogenic effect has been observed. Women who conceived while on treatment gave birth to healthy children in the phase III multicenteric contraceptive trials during research [43–46].
This pilot study has given encouraging results. This drug was observed to be of significant benefit not only in mastalgia but also in regression of fibroadenomas. In our study 40% of the fibroadenomas disappeared, 30% decreased in size, and 30% remained static over a period of 6 months with this treatment.
There were few side effects: a drug-induced rash developed in one patient only; temporary amenorrhoea was observed in 2 patients, and menstrual delay of 7–10 days occurred in 3 patients but reverted back to the normal cycle on withdrawal of the drug after 3 months of treatment.
Centchroman is a nonsteroidal drug found to be effective in the treatment of mastalgia and partially responsive in treating fibroadenomas in a short time period of 3 months without any side effects. There is a need for prospective randomized studies to compare this low-cost drug with minimal side effects with the standard but costly drugs with significant side effects that are being prescribed at present. At our institute the randomized study is ongoing. Let us look forward to a bright future for patients affected with mastalgia.