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REVIEW ARTICLE

A Review of Mastalgia in Patients with Fibrocystic Breast Changes and the Non-Surgical Treatment Options

Khalid Rida Murshid FRCS(C), FACS

Department of Surgery, College of Medicine, Taibah University, Al Madinah Al Munawwarah, Kingdom of Saudi Arabia

Abstract Objectives

The objectives of this study are to review fibrocystic changes of the breast, their causal and associated factors and their correlation to mastalgia, and then to review the available treatment options for mastalgia (caused by fibrocystic changes) short of surgery. Methods The author reviews all the articles obtained from a PubMed research on mastalgia and fibrocystic changes of the breast, published in English over the last 14 years. Results Fibrocystic changes of the breast are common and can be considered as a normal phase of breast development. These changes are sometimes asymptomatic; however, when painful, patients would seek medical advice. Lifestyle changes and the avoidance of certain dietary elements as well as the use of some non-pharmacological agents have shown some

beneficiary effects. In severe cases, stronger pharmacological and hormonal agents are resorted to being more effective but are associated with greater side effects. Conclusion Fibrocystic changes of the breast are common and should not be considered a disease. When painful, reassurance and non-pharmacological measures should be used first as a treatment. Stronger pharmacological and hormonal agents hold more serious side effects. Some of these remedies are supported by good clinical evidence, while others are not. The ideal treatment for mastalgia caused by fibrocystic changes is to be identified by sound recent randomized controlled clinical studies on simple remedies before being performed on stronger ones. Treatment should start with simple lifestyle changes and advance with a stepwise fashion to

stronger remedies only in those where other means fail.

Key words: Fibrocystic breast disease, Fibrocystic breast changes, Fibrocystic breast condition, Mastalgia, Mastodynia.

Journal of Taibah University Medical Sciences 2011; 6(1): 1-18

Correspondence to: Dr. Khalid Rida Murshid Associate Professor of Surgery Department of Surgery, College of Medicine Taibah University,  30001 Al Madinah Al Munawwarah Kingdom of Saudi Arabia +966 4 8460006  +966 4 8461407  [email protected]

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Khalid Rida Murshid

Introduction ‗fibrocystic change‘, an emphasis that has been evolving in the literature3. ibrocystic breast changes as well as F mastalgia are common conditions that Classification and Synonyms women suffer from. They may occur In the 10th revision of the International separately or in combination. The nature of Statistical Classification of Diseases and these changes as well as the associated Related Health Problems, (the ICD-10), factors responsible for their development fibrocystic disease or fibrocystic changes are not fully understood by many who treat also known as chronic cystic mastitis and patients suffering from . fibrocystic mastopathy is classified under Unfortunately, mastalgia caused by ‗benign mammary dysplasia‘ category N60, fibrocystic breast changes is treated by and in case of ‗diffuse cystic mastopathy‘ breast specialists as well as by those not sub-category N60.1. If there is epithelial specialized in breast diseases. This results in proliferation, it is classified under patients receiving inappropriately strong ‗fibrosclerosis of the breast‘ category N60.3. medication with severe side effects, where ‗Mastodynia‘ is classified under N64.44. simpler remedies could have done the job more efficiently. Eponyms This entity (fibrocystic disease of the breast) Breast histology has historically been termed as Bloodgood‘s The life cycle of the breast consists of three disease, Cooper's disease (after Sir Astley main periods: development, mature Paston Cooper), Phocas' disease, Reclus‘ reproductive life, and involution. The breast disease, Reclus‘ syndrome (after Paul is identical in males and females until Reclus), Reclus-Schimmelbusch disease, puberty. After the breast has developed, it Schimmelbusch disease and Tillaux-Phocas undergoes regular changes in relation to the disease5. menstrual cycle that results in an increased rate of cell proliferation during the luteal Are fibrocystic changes and Mastalgia phase leading to an increase in breast size1. synonymous? results in a progressive increase Fibrocystic changes of the breast involve in breast weight till term, and the breast various histological findings in both involutes following pregnancy. Breast asymptomatic and symptomatic women, involution begins at some time after the age and are common in both groups. Fibrocystic of 30 in nulliparous women. During changes and mastalgia are two different involution the breast stroma is replaced by things although they commonly occur fat, so that the breast becomes less together. They can also occur separately, radiodense, softer, and ptotic (droopy). making the association between breast pain Changes in the glandular tissue include the and fibrocystic histology inconsistent6. development of areas of fibrosis, the formation of small cysts (microcysts), and an Mastalgia (Breast Pain) increase in the number of glandular Mastalgia (breast pain) was described in the 7 elements (adenosis)1. This leads to a medical literature as early as 1829 and is a spectrum ranging from normal histologic common complaint amongst women. Most features to features that mainly exhibit of them describe premenstrual mild cyclic patterns of fibrous change and cyst mastalgia (CM) that lasts for 1 to 4 days as 8 9 formation, formerly called fibrocystic ―normal‖ . Recent population based , and 10,11 disease of the breast. Since this histologic breast clinic-based studies suggest that pattern may be evident in up to 50 or even up to 70% of women under 55 experience 60 percent of women without breast disease, breast pain. Although 45% of them report it led Love et al to suggest that fibrocystic minimal to mild symptoms, about 25% ―disease‖ does not exist2. The currently report moderate-to-severe mastalgia lasting accepted term for this condition is for more than 5 days.

2 J T U Med Sc 2011; 6(1) A review of mastalgia in patients with fibrocystic breast disease

Etiology Most agree that CM and tenderness are part What causes fibrocystic breast condition to of the PMS12,15. Luteal-phase symptoms, cause mastalgia? including water retention, negative affect, Researchers have found no clear hormonal impaired concentration and behavior or specific pathological processes that change were significantly greater in women explain cyclical breast pain12. However, with severe CM compared to women certain associations and factors cannot be without breast symptoms. Also, women ignored (Table 1). with severe CM experienced more breast symptoms and negative affects in the Table 1: Factors with possible relation to follicular phase of the menstrual cycle16. A the development of Fibrocystic Changes of study of 30 subjects showed that most the breast. women whose symptoms met the criteria for CM had experienced other premenstrual 17 Factors possibly related to Fibrocystic and somatic symptoms . However, others Breast Changes have found that although premenstrual 1 Age symptoms were common in women with 18 2 CM, only 16% of women in one study , and 9 3 Premenstrual syndrome 22.5 % in another study had sufficient symptoms that met the criteria for both CM 4 Duct ectasia and PMS. 5 Stress

6 Smoking Duct ectasia 7 Caffeine Ultrasonographic measurement of the maximum mean width of the milk ducts Age was 1.8 mm in asymptomatic women, 2.34 Breast pain is most common amongst mm in women with CM, and 3.89 mm in women aged 30–50 years10. women with non-CM (P<0.001). Ductal

width correlated with pain intensity19. Hormones

1. hormonal associations The fact that mastalgia in patients with Other Risk Factors and High Risk fibrocystic changes is related to hormonal Groups events, such as the menstrual cycle, pregnancy, menopause and Stress appears to be a factor as women with therapy suggests a relationship between the severe breast pain seem to have had greater two. incidence of significant life events than women without severe breast pain9. Smoking 2. as well as caffeine intake also seems to be risk In one study 16% of women reported breast factors9. pain as a side effect of therapy and 32% reported the same in cases of combined Clinical Features hormonal therapies13. Other researchers have also identified increased breast density Fibrocystic breasts are lumpy or nodular during hormonal therapy14. On the other and although the breast changes categorized hand, hormonal contraceptive was found to as "fibrocystic" are normal; they can cause be associated with significantly less breast pain and tenderness that is usually mastalgia and premenstrual syndrome related to the period12. This glandular (PMS)9. texture may be finely granular, nodular, or even grossly lumpy. Breast pain and 3. relationship to other premenstrual palpable mass are the symptoms most symptoms frequently described by women presenting to general practitioners or breast clinics20, 21.

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CM accounts for approximately 2/3 of Relationship to breast pain in specialty clinics, whereas non- CM accounts for the remaining 1/322. CM Mastalgia is rarely considered as a typically presents during the third or the presenting symptom of breast cancer6. In fourth decade of life and the symptoms tend one study, the relative risk of Breast Cancer to persist with a relapsing course22. It developing ranged between 0.3 and 0.7 in usually starts during the luteal phase of the patients with breast pain and was menstrual cycle and increases in intensity significantly higher (1.9-3.0) only in patients until the onset of menses, when it aged > 40 years with breast lumps. They dissipates6. Mastalgia may be severe enough concluded that in symptomatic patients to influence usual daily activities11. In spite Breast Cancer risk is strictly related to age of that, mastalgia generally is and independent of the referred underreported. Remission often occurs with symptoms26. Conversely, in a review of 1532 hormonal events such as pregnancy or women with breast pain (when women with menopause. Only 14% of women with CM breast pain as a sole complaint were experience spontaneous resolution; excluded) the risk of breast cancer was however, 42% experience resolution at lower in women having pain incidental to menopause22. The outcome can be another presenting complaint27. In a recent successful in most patients with case-control study of women referred for reassurance, non-pharmacological measures diagnostic breast imaging to evaluate pain, and in some instances one of several there were no differences between the effective medications23. mammographic findings and frequency of malignancy in women with pain compared Breast Pain Assessment with a matched control group undergoing routine screening28. However, because of the Quantifying breast pain may be difficult increased awareness of breast cancer, more because of its variability23,24. Before starting women are seeking professional advice than any therapy for breast pain, patients should ever before23, 29,30,31,32. Classically, breast pain be asked to document the frequency and associated with cancer is unilateral, constant severity of their pain on daily basis for at and intense8. least one menstrual cycle using a visual analog scale. The pain scale is also helpful in Treatments (Table 2) assessing treatment response in mastalgia, which is characterized by the waxing and General waning of symptoms and a high A wide variety of therapies are used, but spontaneous remission rate24. In one study, is the most commonly used by 75% the total breast pain score was found to be of surgeons. Breast specialists tend initially most efficiently estimated by a combination to use methods that are associated with of a visual analog scale, present pain index, fewer side-effects and reserve stronger and quality-of life questions25. These treatments such as danazol and measures are particularly important for CM bromocriptine for more difficult cases. as the diagnosis based on recall of Hormonally active medications are more symptoms is only 65% sensitive, and the effective for patients with CM and are diagnosis based on the prospective breast prescribed only for patients with severe pain diary is 69% specific17. Research prolonged symptoms33,34. criteria for the diagnosis of CM are (1) pain severity greater than 4.0 cm measured on a Nonpharmacological Interventions 10.0-cm visual analog scale and (2) pain Education and reassurance 11 duration of at least 7 days per month . Education and reassurance are integral parts of the management of mastalgia and should be the first-line of treatment35.

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Table 2: Treatment options for mastalgia of the breast. Remedy Evidence For Evidence Other Remarks Against Non-Pharmacological, Non- Nutritional Recommendations Education and reassurance 35 Relaxation Training 3 6 Wearing A Bra 35,3 8 Nutritional Recommendations Dietary Fat Reduction 39 ,4 0 4 1 ,4 2 ,4 3 Dietary Fiber 43 Methylxanthine Restriction 31 Nutritional Supplements and Herbal Agents Vitamin E 46,47,48 35 Soy 54,55 Fish oil 56 Evening Primrose Oil 12,24,33,48, 57, 31,35,41,56,6 Not to be used in patients on 58 0 anticonvulsant therapy. Its safety during pregnancy or lactation has not been established. Flax Seed Oil 35 62 Chasteberry 44,63 Pharmacological Interventions Non-Hormonal Medications Simple Analgesics 35,65,66,67 23 Hormonally Active Medications Oral Contraceptives 69,70,71 68,70,71 , + 72 Progestins Danazol 46,79,80 To reduce side effects reduce the dose once a response is achieved and/or luteal-phase administration. It is contraindicated in women with H/O thromboembolic disease and potentially teratogenic. Dopamine 1-Bromocriptine 84 86 Side effects less if the drug is taken with meals. , seizures and death have been reported after its use to inhibit lactation, and the US FDA has withdrawn its licence for this indication. 2-Lisuride 87 3-Quinagolide 88 Selective Estrogen Receptor Modulators (S.E.R.M.) 1- 80,91,92 8,93 Tamoxifen has a risk of potentially serious adverse effects and is contraindicated in pregnancy because of potential teratogenicity. 2-Toremifene 94 -Releasing Adverse effects related to the Hormone Agonists: hypoestrogenic state produced by these medications are frequent and often severe Buserelin 96 High decline in trabecular bone mineral density.

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Psychological Associations and Relaxation The effectiveness of dietary interventions to Training reduce breast pain are continually The potential psychological origin of breast undergoing investigations. The following pain has been explored throughout the have recently been studied. medical literature. As far back as 1829, Sir Astley Cooper wrote that women seeking Dietary Fat advice for breast pain usually had ―a Lower dietary fat intake has been associated nervous and irritable temperament.‖7. More with less severe mastalgia symptoms39. By recently, anxiety and other psychological reducing dietary fat, other parameters that disorders have been found by others to be may be related to mastalgia are altered, more frequent among women with including mammographic breast density40. mastalgia compared with asymptomatic However some claim that the effect of women36. In another study, women with decreased dietary fat intake on other breast pain had, in addition, increased fibrocystic changes of the breast is limited somatization, and history of emotional and also claim that in order to derive benefit abuse compared with women with breast from this approach, women must decrease lumps alone37. This led some to explore the fat intake to less than 20% of total daily effect of relaxation on breast pain. H.Fox et caloric intake41. This reduction in fat intake, al found that approximately 61% of women in addition to being difficult to sustain, may who listened to relaxation audiocassettes not be optimal in some cases42. daily for 4 weeks experienced substantial or complete relief of breast pain compared to Fruits,Vegetables,andDietaryFiber 25% of controls (P< 0.05). The subjects also The results of T.E. Rohan et al suggest that a had substantially more pain-free days and modest reduction in fat intake and an less anxiety than controls36. increase in fruit, vegetable, and grain intake Stop Smoking does not alter the risk of benign proliferative Patients with mastalgia should stop, or at breast disease43. least reduce the number of cigarettes taken daily, based on a study that identified Methylxanthine (Caffeine) Restriction smoking as being a factor associated with Caffeine reduction or elimination is mastalgia9. recommended by many specialists to

Wearing A Bra alleviate breast pain, and although many B.R. Mason et al have hypothesized that women reported that it alleviates their breast pain is mainly associated with the breast pain, clinical studies have not shown 6 movement of breast tissue, and have shown consistent findings . Since caffeine is present that wearing an external breast support in coffee, tea, chocolate and cola, this makes reduced absolute vertical movement and it difficult to completely eliminate from the maximum downward deceleration force on diet; even in clinical trials. It also puts a big the breast. Breast support also reduced question mark on studies performed using perceived pain. Of the three garments total elimination of methylxanthines from examined in this study, the fitted sports bra the diet for long periods. In addition, some provided superior support resulting in pain recommend that women with breast pain reduction38. V. Rosolowich et al also agree should not be advised to reduce caffeine 35 that the use of a well-fitting bra that intake . An association between provides good support should be methylxanthines (caffeine or theophylline) considered for the relief of mastalgia35. and breast symptoms of pain, tenderness, nodularity, has been reported by other investigators9. In an uncontrolled study, Nutritional Recommendations 61% of women with breast pain who

substantially decreased caffeine intake for 1 Dietary Change year had decreased pain or complete relief31.

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Many of us will continue to advise patients for six months may decrease the severity of to practice some restriction in their caffeine CM mastalgia48. intake on the basis of clinical experience and the few studies with breast pain as a discrete Soy outcome, especially in women with Soy is a rich source of the isoflavones problematic breast pain who have moderate genistein and daidzen, which exert their to heavy caffeine consumption9. effect by binding to estrogen receptors49. In premenopausal women, this increases the Nutritional Supplements and duration of the follicular phase of the Herbal Agents menstrual cycle and delays menstruation. In addition, it may decrease midcycle surges of Interest is growing in herbal agents, luteinizing and follicle-stimulating 43 50 nutritional supplements and alternative hormones and decrease levels . strategies for treatment of breast pain6. Others have found that flavonoids exhibit 51 Patients frequently use herbs and dietary significant hormone activity . Some supplements to treat chronic conditions that studies of soy on breast epithelium revealed 52 are poorly responsive to prescription drugs, markers of increased proliferation , 53 or when prescription drugs carry a high side whereas others did not . R.M. Fleming effect burden44. Physicians must be conducted a study to examine the effect of cognizant that herbal agents and nutritional daily soy protein consumption which supplements are not standardized or showed both objective and subjective monitored for adulteration45. Potential reduction in both breast tenderness and 54 interaction with medications and other fibrocystic disease . In another study, the herbal medicinal also must be considered. reduction of pain was significantly better 55 than placebo . Vitamins Vitamin E (α-tocopherol) Fishoil Vitamin E is by far the most commonly J. Blommers et al studied the effect of both used and most commonly studied vitamin EPO and fish oil on breast pain and to use as a treatment for breast pain. While concluded that neither EPO nor fish oil some go as far as stating that vitamin E offered clear benefit over control oils in the 56 should not be used for the treatment of treatment of mastalgia . mastalgia35, when comparing vitamin E to danazol, Khanna et al found that the Evening Primrose Oil (EPO) treatment with vitamin E showed a 41% There is some evidence suggesting that response rate with minimal side-effects, women with mastalgia have increased levels while treatment with danazol showed a of saturated fatty acids and reduced 72.1% response rate but was associated with proportions of essential fatty acids, side-effects in one third of the patients46. especially of gamma-linolenic acid (GLA). More recently, a study concluded that a 2- These abnormal fatty acid profiles may month prescription of vitamin E has positive cause hypersensitivity of the breast therapeutic effects on cyclic mastalgia. epithelium to circulating hormones. GLA is Given its lack of significant side effects, believed to restore the vitamin E can be considered a safe saturated/unsaturated fatty acid balance alternative to hormonal therapies currently and decrease sensitivity to steroidal 41 used in the treatment of cyclic mastalgia47. hormones . Also, low levels of the GLA Also, Pruthi et al concluded that daily doses metabolite, dihomogamma-linolenic acid of 1,200 IU vitamin E, 3,000 mg Evening may affect breast sensitivity to prolactin via 41 Primrose Oil (EPO), or vitamin E and EPO prostaglandins . EPO is rich in Omega-6 in combination at these same dosages taken Fatty Acids. GLA is an omega-6 fatty acid found primarily in vegetable oils including EPO. EPO typically contains 9% GLA by

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weight57. For women with CM who elect Theoretical mechanisms of the actions of treatment, EPO has been advocated by Vitex agnus-castus are that it binds to many as an initial option12,24,33,58, and several opioid, histamine, and estrogen receptors63, have reported efficacy in the treatment of or acts via dopaminergic and prolactin- breast pain with low adverse effect rates48,57. suppressant effects64. In a study of the fruit One randomized controlled trial found that extract of Vitex agnus-castus (chaste tree most adverse effects were gastrointestinal. berry) in 1634 subjects for 3 menstrual However, there were no significant cycles, 93% of the subjects reported differences in rates between the EPO plus improvement in symptoms related to multivitamins and the placebo plus premenstrual syndrome and 81% of subjects multivitamins group59. Proponents of its rated their status after treatment as much usefulness suggest the dosage for breast better or very much better. Few adverse pain to be 3000 mg/d (in divided doses), effects were identified63. and claim that patients may continue to improve after 3 months of treatment and Pharmacological Interventions therefore recommend assessing response to therapy after at least 6 months57. GLA Simple Analgesics however, may affect the seizure threshold; It is very likely that patients would have for this reason, some researchers advise already used simple mild over the counter against its use in patients requiring analgesics before seeing their doctor to anticonvulsant therapy45. In addition, the prescribe. In one study, topical application safety of EPO during pregnancy or lactation of the anti-inflammatory has not been established. Its benefits have agents diclofenac and piroxicam yielded been found in some studies to be only satisfactory relief in 81% of 26 women with modestly better than placebo, and some severe cyclic, noncyclic, and surgical scar– question its therapeutic value for breast related breast pain65. In another study, pain31,35,41,56,60. Rosolowich et al recommend that topical

non-steroidal anti-inflammatory gel, such as Borage Seed Oil diclofenac 2% in pluronic lethicin organogel, Although borage is the highest known be considered for pain control for localized plant-based source of gamma-linolenic acid treatment of mastalgia35. S. Qureshi and N. (GLA), the seed oil content being between Sultan found topical non-steroidal anti- 26-38% and the oil is often marketed as inflamatory drugs (NSAIDs) to be a safe, "starflower oil" or "borage oil" for uses as a effective, rapid and acceptable mode of GLA supplement61, I have not come across treatment for CM and non-CM in addition any recent studies on its use in mastalgia. to being superior to EPO in all aspects66. A

prospective, randomized, blinded, placebo- Flax Seed Oil controlled study of topical diclofenac Although V. Rosolowich et al claimed that showed significant pain reduction in flaxseed should be considered as a first-line patients with CM as well as those with non- treatment for CM35, E. Basch et al performed CM compared with placebo. No adverse an extensive electronic search in an attempt effects occurred67. Conversely, another to evaluate the scientific evidence on study of topical ibuprofen used in clinical flaxseed. They found that most of the practice determined no beneficial effect on available evidence investigates the efficacy breast pain23. of alpha-linoleic acid found in flaxseed compared with fish oil, and state that almost Hormonally Active Medications all of the available studies are poor quality Most researchers favor less aggressive that do not support recommendations for measures before hormonal agents are any condition at this time62. embarked upon. However when these

measures fail, danazol, bromocriptine, or Chasteberry (Vitex agnus-castus)

8 J T U Med Sc 2011; 6(1) A review of mastalgia in patients with fibrocystic breast disease tamoxifen are the most widely resorted to, while focusing on a balance between relief Hormonal Supplements of pain and side effects of these hormonal agents. Many oral contraceptives list breast Progesterone, Progestogens and Progestins pain and tenderness as potential adverse A progestin is a synthetic that effects. Eliminating or decreasing the dose of has progestinic effects similar to estrogen in an oral contraceptive or progesterone. The two most common uses hormone regimen is often effective in of progestins are for clinical practice, particularly if the onset of (either alone or with an estrogen) and to symptoms is temporally related to the prevent endometrial hyperplasia from initiation or change of medication6. unopposed estrogen in hormone replacement therapy61. In a controlled, Oral Contraceptives (OCs ), Estrogen, and randomized, double-blind, parallel-group Progesterone study by UH Winkler et al, 31 women with While some studies of low-dose OCs (20 μg mastopathy/mastodynia were treated with ethinyl estradiol) have found no increased the progestins medrogestone or breast symptoms compared with placebo68. (10 mg/day) from day 14 to Others have shown that many women day 25 for six cycles. They concluded that reported a reduction in severity and cyclic administration of these low-dose duration of cyclic breast discomfort and progestins proved to be an effective and safe PMS while taking OCs9. A multicenter case- treatment of mastodynia and mastopathy, control study was performed on women evidenced by improvement in objective receiving acetate parameters in more than 50% of patients. (Depo-Provera) for contraception compared Improvement was particularly marked in with age matched controls. Frequent breast women with low progesterone levels in the pain and medication use for breast pain second half of the cycle. After six treatment were noted in 9% and 5%, respectively, of cycles, 75% of the patients treated with women using Depo-Provera compared with dydrogesterone and 86% of the patients 21% and 9% of women in the control treated with medrogestone were completely group69. TE Rohan and AB Miller pain-free72. investigated the association between OC use and the risk of benign breast disease (BBD), Hormone Replacement Therapy (HRT) overall and by histological subtypes, within Although HRT is not( in itself) a treatment the 56,537 women in the Canadian National for mastalgia or fibrocystic changes of the Breast Screening Study (NBSS). There was breast, it is mentioned here due to its strong an inverse association between the use of causative relationship with breast changes. OCs and the risk of all types of BBD In an attempt to study the association combined. The risk of BPED with atypia was between HRT use and the risk of benign increased somewhat in association with OC proliferative epithelial disorders of the use for the use of more than 7 years, but not breast (BPED), TE Rohan and AB Miller in a dose-dependent manner70. In a follow found that in post-menopausal women, in up study on the 17,032 women in the whom most of the reported use occurred, Oxford-Family Planning Association study there was a positive association between using different methods of contraception, M duration of HRT use and the risk of BPED73. Vessey and D Yeates found that low-dose LA Mattsson and T Sporrong reported a combined OCs containing <50 mcg estrogen lower incidence of mastalgia during appear to reduce the risk of hospitalization treatment with low dose regimen HRT for fibroadenoma and chronic cystic disease compared to high doses. They suggested for as well as older preparations containing cases requesting HRT to begin with low higher doses of estrogen. The apparent dose formulations since these doses are protective effect was not present for women sufficient for the majority of women74. MC using progestogen-only OCs71. Yenen et al found that (a synthetic

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steroid hormone acting as an at all treatment of mastalgia6. While employing five of the Type I steroid hormone danazol in the management of cases with receptors61), was associated with a decrease endometriosis, an unexpected voluntary in cyst dimensions which was statistically comment patients frequently offered was significant in benign cystic mastopathy that breast pain, nodularity and patients compared to other hormone premenstrual engorgement were alleviated. replacement therapy regimens75. A. This finding led some workers to the Ozdemir et al when studying treatment of women with mammary mammographic and ultrasonographic dysplasia with danazol. Danazol changes in the breast related to HRT showed subsequently was found, in controlled that mammographic density changes related clinical trials, to considerably relieve breast to HRT are dependent on the selected pain and tenderness in the women treated79. hormone regimen. The degree of density In addition, comparative studies were increase was evidently minimal in tibolone conducted. In one such study, treatment users compared to others. Formations of with vitamin E showed 41% response rate breast cysts or solid lesions did not seem to with minimal side-effects while treatment be related to HRT76. In a study by with danazol showed 72.1% response rate E.Lundström et al, HRT regimens were but was associated with side-effects in one shown to have different effects on the third of the patients46. Unfortunately, normal breast. An increase in adverse effects occur with the use of mammographic density was noted much danazol. They are dose related and more commonly among women taking primarily androgenic, including menstrual continuous combined HRT (40%) compared irregularity or , acne, hair loss, to those using oral low-dose estrogen (6%) decrease in voice pitch, weight gain, and transdermal (2%) treatment. They found headache, , rash, anxiety and the increase in density to be apparent as depression. Attempts at reducing side early as the first visit after starting HRT. effects included reducing the dose once a During long-term follow-up, there was very response is achieved and/or luteal-phase little change in mammographic status77. administration of danazol (confining M.D.Cahn et al stated that the use of HRT treatment to the 2 weeks preceding may promote lesions that predispose to menstruation). These were shown to relieve cancer, and recommended that patients premenstrual breast pain in women with treated with HRT undergo vigilant PMS without increased adverse effects surveillance by way of examination and compared with placebo80. However, danazol mammography78. A change in dose, is contraindicated in women with a history formulation, or scheduling should be of thromboembolic disease, is potentially considered for women on HRT, and HRT teratogenic and can interfere with oral may be discontinued if appropriate35. Also, contraception so that women who could contraception is important during treatment become pregnant should use mechanical and should be discussed with patients6. contraception33,58,81.

Powerful Drugs With Hormonal Effects Anti-Progestins Antigonadotropins; Danazol Danazol is a derivative of the synthetic Gestrinone is a synthetic steroid, reported to steroid , a modified . have androgenic, antioestrogenic, and It was approved by the U.S. Food and Drug antiprogestogenic properties in a way Administration (FDA) as the first drug to similar to danazol82. Gestrinone reduces specifically treat endometriosis in the early ovarian hormone secretion, decreases 1970s61. It suppresses gonadotropin follicular development and suppresses the secretion, prevents luteinizing hormone midcycle surge of follicle-stimulating surge, and inhibits ovarian steroid hormone and luteinizing hormone83. formation and is approved by the FDA for Adverse effects are primarily androgenic,

10 J T U Med Sc 2011; 6(1) A review of mastalgia in patients with fibrocystic breast disease the most common complaints being acne, Prolactin levels decreased significantly in seborrhea and weight gain. However, I have the group receiving lisuride, which not come across any recent study of value correlated well with pain resolution87. on its use in the treatment of mastalgia. 3. Quinagolide Dopamine Agonists Quinagolide is a selective, Dopamine The rationale behind the use of dopamine receptor D2 agonist that is used for the agonists to treat breast pain is the increase in treatment of elevated levels of prolactin61. In thyrotropin-induced prolactin secretion a pilot on 52 patients, 75 microg detected in women with mastalgia. Quinagolide given once per day was administered for the treatment of CM. 1. Bromocriptine Linear analogue charts were used for the Bromocriptine is a dopamine agonist which assessment of response. Decrease in breast was found to significantly decrease breast pain, heaviness, tenderness and serum pain, heaviness, and tenderness84. Clinical prolactin level on the one hand, and improvement generally occurs in 47% to increases in the serum estradiol and 88% of symptomatic women and is often progesterone levels on the other hand were sustained after cessation of the medication6. noted after 3 and 6 months administration Some researchers advocate using the and were statistically significant. The prolactin response to thyrotropin-releasing beneficial effect of Quinagolide also lasted hormone (see below) to predict response for after the cessation of treatment. Adverse bromocriptine84. This was proved useful in a effects like nausea, low blood pressure, study using 2.5 mg b.i.d. of bromocriptine dizziness and constipation were rarely for 3-6 months, 73.6% of the subjects with an reported88. abnormal response experienced effective mastalgia treatment compared with 23.5% of Selective Estrogen Receptor subjects with a normal response, the difference was statistically significant84. Modulators (S.E.R.M.) Bromocriptine side effects seem to be less if 1. Tamoxifen the drug is taken with meals85. However, Tamoxifen is an antagonist of the estrogen other side effects are much more serious. receptor in breast tissue via its active Strokes, seizures and death have been metabolite, hydroxytamoxifen and behaves reported after the use of bromocriptine to as an agonist In other tissues such as the inhibit lactation, and the US FDA has endometrium.. Hence tamoxifen may be withdrawn its licence for this indication86. characterized as a mixed

61 2. Lisuride agonist/antagonist ; and the use of it in Lisuride is an antiparkinson agent of the iso- large numbers of premenopausal women in ergoline class, chemically related to the breast cancer prevention trials has increased dopaminergic ergoline Parkinson's drugs familiarity with this medication in younger 89,90 and is used to lower prolactin61. In a double- women without breast cancer . blind randomized prospective study on 60 Tamoxifen 10 mg daily or danazol 200 mg premenopausal women with premenstrual daily should be considered when first-line 35 mastalgia, where the study and control treatments of mastalgia are ineffective . groups consisted of 30 women each. The Tamoxifen was found to be effective in patients were given one tablet daily (0.2 mg) reducing pain in women with CM and also, of lisuride maleate or placebo orally for 2 but to a lesser degree, in women with non- 80,91 months. Severity of mastalgia was evaluated CM . R. Grio et al, in a randamised using the visual analog scale. Mastalgia controlled study on 88 women, aged 22–44 subsided significantly in women receiving years, found that 8 months of tamoxifen lisuride maleate compared with controls, increased the proportion of women who and there were no significant side effects. achieved complete recovery compared with

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placebo (90% with tamoxifen verses 0% with toremifene citrate, 30 mg daily, and 91 a placebo)92. Tamoxifen has a risk of placebo tablet for 3 menstrual cycles and potentially serious adverse effects, with the were followed up for breast pain score and principal concerns being deep venous adverse events. All women recorded breast and . Also, pain daily on a visual analogue scale chart. hot flashes, nausea, menstrual irregularity, More women reported a reduction of 50% or vaginal dryness or discharge, and weight more in pain scores with toremifene gain have been associated with tamoxifen compared with placebo (69.2% v 31.9% p < treatment6. 0.001). Among the patients with CM, the Adverse effects occurred more frequently response rate for toremifen was 76.7% v with tamoxifen 20 mg than with tamoxifen 34.8% for placebo (p<.001). In contrast, the 10 mg between days 15 and 25 of the response rate of patients with non-CM was menstrual cycle91. And when comparing 48.1% for toremifene and 24.0% for placebo tamoxifen dosages and duration for breast (p= .09). The RCT found that women in the pain, the 10 mg/d dosage of tamoxifen was toremifene group reported adverse effects as effective as the 20 mg/d dosage with (menses disturbances, dizziness, vaginal fewer adverse effects91. One outpatient discharge, and nausea), slightly but not based randomized controlled trial (RCT) on significantly higher than the placebo group 93 women with severe CM compared three (50.5% v 42.9% p = 0.45). Showing that treatments over 6 months: danazol 200 mg toremifene effectively relieves moderate and daily, tamoxifen 10 mg daily, and placebo. severe CM and tends to exert a positive The RCT found that tamoxifen was more therapeutic effect on non-CM, without effective than danazol, both at the end of increasing the incidence of intolerable treatment and 12 months after treatment. adverse event94. However, 4 women taking tamoxifen withdrew from the study owing to adverse Gonadotropin-Releasing Hormone Agonists effects of treatment, compared with 3 of A gonadotropin-releasing hormone agonist those taking danazol. Reported adverse (GnRH agonist) is a synthetic peptide effects included an increase in weight (31% modeled after the hypothalamic with danazol v 0% with tamoxifen), neurohormone GnRH that interacts with the deepening of the voice (13% with danazol v GnRH receptor to elicit the release of the 0% with tamoxifen), menorrhagia (13% with pituitary hormones FSH and LH61. As a danazol v 6% with tamoxifen), and muscle result, these agents reliably decrease (9% with danazol v 0% with estrogen levels in women. In addition, tamoxifen), hot flushes (12% with danazol v extremely low levels of progesterone, 25% with tamoxifen), and vaginal discharge ovarian , and prolactin result95. (9% with danazol v 16% with tamoxifen; P Although the use of GnRH agonists is values not reported)80. Nonetheless, promising, few data are currently available tamoxifen, like the other hormonal to support their clinical use for treatment of interventions, should be reserved for mastalgia. They have troublesome and women with severe mastalgia refractory to potentially serious adverse effects that must other measures6,8. It should be administered be considered in future studies to define under close supervision and for a limited their therapeutic role for breast pain6. period of time8. However, tamoxifen is Adverse effects related to the contraindicated in pregnancy because of hypoestrogenic state produced by these potential teratogenicity93. medications are frequent and often severe, including hot flashes, headaches, nausea, 2. Toremifene fatigue, depression, anxiety, irritability, Toremifene citrate is a S.E.R.M. which helps vaginal dryness, and decreased libido. oppose the actions of estrogen in the body61. Decline in trabecular bone mineral density is In a double-blind RCT, 104 patients with as high as 6% within 6 months of treatment moderate to severe mastalgia received

12 J T U Med Sc 2011; 6(1) A review of mastalgia in patients with fibrocystic breast disease with the GnRH agonist Buserelin. Although and should not be considered a disease but usually reversible, treatment duration is rather a phase of breast development and limited by this effect96. involution. Fibrocystic changes are occasionally associated with breast pain. Other Considerations Mastalgia caused by fibrocystic changes has been treated by a vast array of remedies The Thyrotropin-Releasing Hormone (TRH) ranging from simple re-assurance and a Prolactin (PRL) Response Test (TRH Test) change in lifestyle, to non-pharmacological Using serial measurements of prolactin and pharmacological agents, the latter may plasma levels after an intravenous injection be associated with serious side effects. Some of TRH, (TRH test), patients were divided in of these remedies are supported by good two groups: clinical evidence, while others continue to be 1- Patients with abnormal PRL response to used simply because the treating physician TRH feels his/her patients respond to it. The 2- Patients with normal PRL response to ideal treatment for mastalgia caused by TRH fibrocystic changes remains to be identified N. Rea et al found that bromocriptine by sound recent randomized controlled treatment, 2.5 mg b.i.d. for 3-6 months, was clinical studies. These studies should be effective in 73.6% of patients with abnormal done on the simplest of remedies before TRH test and in 23.5% of patients with being performed on the stronger remedies normal TRH test: the difference was with considerable side-effects. Hopefully, statistically significant. On the other hand, the results revealed by these studies will 76.9% of patients with either normal TRH open the path towards a systematic test or those resistant to bromocriptine approach to the treatment of a common therapy had a favorable response to condition which many women suffer (or are percutaneous progesterone and systemic deemed to suffer) from. Treatment should NSAIDs. These results seem to confirm the start with simple lifestyle changes and hypothesis that PRL response to TRH could advance in a stepwise fashion to abstinence be used to identify patients affected with from certain substances to mild remedies CM that are likely to benefit by and finally to stronger remedies only in bromocriptine treatment84. those where other means fail. Only then can this condition be conquered with the least Sodium Iodide, Protein-Bound Iodide, And adverse effects. Molecular Iodine L. Patrick claims that although above the References established safe upper limit of 1 mg, 3 to 6mg doses of iodine are safe and studies 1. Dixon JM, Mansel RE. ABC of breast using these relatively high doses of iodine to diseases. Congenital problems and treat fibrocystic breast disease may reveal an aberrations of normal breast important role for iodine in maintaining development and involution. BMJ. normal breast tissue architecture and 1994 Sep 24; 309 (6957):797-800. function. He also suggests that iodine may 2. Love SM, Gelman RS, Silen W. also have important antioxidant functions in Fibrocystic ―disease‖ of the breast — a breast tissue and other tissues that nondisease? N Engl J Med 1982; 307: concentrate iodine via the sodium iodide 1010-1014. symporter97. 3. Marchant DJ. Benign breast disease. Obstet Gynecol Clin North Am. 2002; Conclusion 29: 1-20.

4. Disorders of breast (N60-N64) in ICD- 10.http://apps.who.int/classifications/ Fibrocystic changes of the breast commonly affect women in their third or forth decades apps/icd/icd10online/

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5. Who Named It? premenstrual symptoms in women http://www.whonamedit.com/synd.cf with severe cyclic mastopathy. Am J m/1891.html Obstet Gynecol. 1997; 176: 998-1005. 6. Smith RL, Pruthi S, Fitzpatrick LA. 17. Tavaf-Motamen H, Ader DN, Browne Evaluation and management of breast MW, Shriver CD. Clinical evaluation of pain. Mayo Clin Proc. 2004; 79(3): 353- mastalgia. Arch Surg. 1998; 133: 211- 372. 213. 7. Cooper A. Illustrations of the Diseases 18. Ader DN, Shriver CD, Browne MW. of the Breast, Part 1. London, England: Cyclical mastalgia: premenstrual Longman, Rees, Orme, Brown & syndrome or recurrent pain disorder? J Green; 1829. Psychosom Obstet Gynaecol. 1999;20: 8. Millet AV, Dirbas FM Clinical 198-202. management of breast pain: a review. 19. Peters F, Diemer P, Mecks O, Behnken Obstet Gynecol Surv. 2002; 57(7):451- LJ. Severity of mastalgia in relation to 461. milk duct dilatation. Obstet Gynecol. 9. Ader DN, South-Paul J, Adera T et al. 2003; 101: 54-60. Cyclycal mastalgia: Prevalence and 20. BRIDGE Study Group. The associated health and behavioral presentation and management of breast factors. J Psychosom Obstet Gynecol symptoms in general practice in South 2001; 22: 71–76. Wales. Br J Gen Pract. 1999; 49: 811- 10. Ader DN, Shriver CD. Cyclical 812. mastalgia: Prevalence and impact in an 21. Barton MB, Elmore JG, Fletcher SW. outpatient breast clinic sample. J Am Breast symptoms among women Coll Surg 1997;185: 466–467. enrolled in a health maintenance 11. Ader DN, Browne MW. Prevalence and organization: frequency, evaluation, impact of cyclic mastalgia in a United and outcome. Ann Intern Med. States clinic-based sample. Am J Obstet 1999;130:651-657. Gynecol 1997; 177: 126–132. 22. Davies EL, Gateley CA, Miers M, 12. Norlock FE. Benign breast pain in Mansel RE. The long-term course of women: a practical approach to mastalgia. J R Soc Med. 1998;91: 462- evaluation and treatment. J Am Med 464. Womens Assoc. 2002 Spring;57(2):85- 23. Breast pain: mastalgia is common but 90. often manageable. Mayo Clin Health 13. Davies GC, Huster WJ, Lu Y, Plouffe L Lett. April 2000; 18:6. Jr, Lakshmanan M. Adverse events 24. Morrow M.The evaluation of common reported by postmenopausal women in breast problems. Am Fam Physician. controlled trials with raloxifene. Obstet 2000 Apr 15;61(8): 2371-2378 Gynecol. 1999; 93: 558-565. 25. Khan SA, Apkarian AV. The 14. Lundstrom E, Wilczek B, von Palffy Z, characteristics of cyclical and Soderqvist G, von Schoultz B. noncyclical mastalgia: a prospective Mammographic breast density during study using a modified McGill Pain hormone replacement therapy: Questionnaire. Breast Cancer Res differences according to treatment. Am Treat. 2002;75: 147-157. J Obstet Gynecol. 1999; 181: 348-352. 26. Lumachi F, Ermani M, Brandes AA, et 15. Klock SC. Psychological aspects of al. Breast complaints and risk of breast women‘s reproductive health. In: Ryan cancer: population-based study of 2,879 KJ, Berkowitz RS, Barbieri RL, Dunaif self-selected women and long-term A, eds. Kistner‘s Gynecology and follow-up. Biomed Pharmacother. Women‘s Health. 7th ed. St Louis, Mo: 2002; 56: 88-92. Mosby; 1999:519-539. 27. Khan SA, Apkarian AV. Mastalgia and 16. Goodwin PJ, Miller A, Del Giudice ME, breast cancer: a protective association? Ritchie K. Breast health and associated [published correction appears in

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