Etiology and Management of Benign Breast Disease

The aberrations of normal development and involution (ANDI) classification of benign breast disorder (BBD) provides an overall framework for benign conditions of the breast that encompasses both pathogenesis and the degree of abnormality. It is a bidirectional framework based on the fact that most BBDs arise from normal physiologic processes ( Table 14.1 ). The horizontal component defines BBD along a spectrum from normal to mild abnormality (“disorder”) to severe abnormality (“disease”). The vertical component defines the pathogenesis of the condition. Together these two components provide a comprehensive framework into which most BBDs can fit. This scheme was recommended by an international multidisciplinary working group in 1992.

Table 14.1

Aberrations of Normal Development and Involution Classification of Benign Breast Disease

	Normal	Disorder	Disease
Early reproductive years (age 15–25)	Lobular development	Fibroadenoma	Giant fibroadenoma
	Stromal development	Adolescent hypertrophy	Gigantomastia
	Nipple eversion	Nipple inversion	Subareolar abscess/mammary duct fistula
Mature reproductive years (age 25–40)	Cyclical changes of menstruation	Cyclical mastalgia	Incapacitating mastalgia
	Epithelial hyperplasia of pregnancy	Nodularity
		Bloody nipple discharge
Involution (age 35–55)	Lobular involution	Macrocysts
		Sclerosing lesions
	Duct involution/dilation sclerosis	Duct ectasia	Periductal mastitis/abscess
	Epithelial turnover	Nipple retraction	Epithelial hyperplasia with atypia
		Epithelial hyperplasia

Breast Pain

Although mastalgia is one of the most commonly reported symptoms in women with breast complaints at dedicated breast clinics or general practice, it is still underreported and poorly characterized. In a 2014 general population survey of 1659 women, more than half (51.5%) experienced breast pain, with 17% reporting a severity of pain greater than 7 out of 10. Approximately 70% of women suffer from mastalgia in their lifetime. Maddox and Mansel reported that only 50% of women with breast pain had consulted a family physician, and fewer had visited a dedicated breast clinic. Because of the increasing awareness of breast cancer and the possibility that mastalgia may indicate disease, as well as the effect mastalgia has on the quality of life, more women than ever are seeking help for breast pain. Treatment usually balances management of this complaint with the side effects of treatment itself. Fakhravar and colleagues report that up to 85% of women with breast pain will show alleviation of their symptoms after receiving reassurance that the pain is not stemming from a malignant source. The remaining 15% will require treatment apart from reassurance, in order to address the negative impact on physical activity, sexual activity, and quality of life in general. More than 90% of patients with cyclic mastalgia and 64% of patients with noncyclic mastalgia can obtain relief by using a combination of nonprescription and prescription drugs.

Clinical Assessment

The degree, severity, and relationship of breast pain to the menstrual cycle are best assessed with the use of a daily breast pain chart that uses a visual analog scale. This chart should be kept during at least two menstrual cycles. Mild breast pain (<3 on the scale) that lasts fewer than 5 days before a menstrual cycle is considered normal. The extent to which mastalgia disrupts the patient’s normal lifestyle in terms of sleep, work, and intimacy provides a useful assessment of severity. A thorough history that includes diet, methylxanthine intake, and use of new medications (especially hormones, antidepressants such as serotonin reuptake inhibitors, and cardiac medications such as digoxin and cimetidine) or illicit drugs should be taken, and a history of recent stress should be recorded. Other conditions should be excluded, such as possible referred pain, from sources such as shoulder bursitis, cervical radiculopathy, costochondritis, myocardial ischemia, lung disease, hiatal hernia, and cholelithiasis.

Patients are reassured that they do not have breast cancer only after clinical examination and mammography are performed and reveal no malignancy. Fortunately, isolated breast pain is an uncommon symptom of malignancy. In a study by Noroozian and colleagues of 1386 women with mammograms performed for breast pain, only 1.8% were found to have breast cancer. In a more recent study performed by Altintas and Bayrak, breast cancer incidence in patients with mastalgia was 0.8%, with the majority of those patients being postmenopausal (80%). Mastalgia in this study was found to be noncyclic in nature. Furthermore, ultrasonography can be a useful adjunct to evaluate focal pain, especially in young women with dense breasts, as 23% of breast pain patients have cysts or benign masses as the root cause.

No study to date has reported an increased risk of breast cancer with cyclic mastalgia; however, the uneasiness and fear of breast cancer caused by pain should not be ignored. Initial evaluation should exclude breast pain from localized benign lesions of the breast that may require needle aspiration or surgical therapy, such as painful cysts, fibroadenomas, subareolar duct ectasia, and fibrocystic changes.

Classification

Classification of mastalgia provides a baseline measurement of pain and severity, dividing symptoms into the categories of cyclic mastalgia, noncyclic mastalgia, and chest wall pain. This distinction is important because presentation, occurrence of spontaneous remission, and likelihood of a response to treatment differ for these three conditions.

Cyclic mastalgia accounts for approximately 67% of cases, and usually first presents during the third decade of life as dull, burning, or aching pain. One breast is usually involved to a greater extent than the other, and the pain may be sharp and shooting, with radiation to the axilla or arm because of glandular entrapment of the intercostobrachial nerve. Cyclic mastalgia usually starts in the upper outer quadrant of the breast 5 days or more before the menstrual cycle, although severe pain can occasionally persist throughout the cycle. Exacerbation of symptoms just before menopause can also occur. Resolution of symptoms at menopause occurs in 42% of women; however, spontaneous resolution before menopause occurs in 14% of patients.

Noncyclic mastalgia tends to occur much less frequently, in 26% of patients, and peaks during the fourth decade of life. The duration of noncyclic mastalgia tends to be shorter, with spontaneous resolution occurring in nearly 50% of patients. In contrast to cyclic mastalgia, noncyclic mastalgia is almost always unilateral. Exacerbations of pain occur for no apparent reason and are difficult to treat.

A careful clinical breast examination should also rule out a small, thrombosed vein that can present as persistent breast pain. Mondor disease, superficial thrombophlebitis of the breast, typically presents as a painful, tender, palpable cord. Although the exact etiology is unknown, risk factors include trauma, surgery, local intravenous access, and smoking. Ultrasound is the recommended mode of diagnostic imaging, with sonogram revealing an anechoic, noncompressible tubular structure with areas of narrowing and absence of flow on Doppler ; however, diagnosis can often be made by clinical findings alone. Rates of associated malignancy are low, but underlying cancer should be excluded by imaging and clinical findings. Pain is generally self-limited with resolution in 2 to 8 weeks, although supportive treatment may include antiinflammatories and warm compresses.

Mastalgia from other origins includes scapular bursitis, costochondritis, lateral extramammary pain syndrome, cervical radiculopathy, or other nonbreast causes. Chest wall pain from these etiologies is almost always felt either on the lateral chest wall or at the costochondral junction. Tietze syndrome, which commonly affects the second and third costochondral junctions, can manifest as focal, medial breast pain. Musculoskeletal inflammation, especially scapular bursitis, can present as referred pain to the breast and is often diagnosed by improvement with a scapular trigger point injection of anesthetic and treatment with an injection of steroid. Neurogenic pain is much more difficult to diagnose and treat. If pain of neurogenic origin is suspected, reassurance in the setting of physical therapy for range of motion, strengthening, and desensitization is a reasonable starting point, followed by oral medications such as analgesics, anticonvulsants, and antidepressants.

Survivors of breast cancer who have undergone breast-conserving therapy reported significantly higher rates of breast pain than those without breast cancer. In a study by Wang and colleagues, approximately 25% to 60% of women who had undergone breast surgery and survived breast cancer reported persistent breast pain. This persistent pain has also been associated with reduced quality of life and functional impairment. Two nonmodifiable factors showing a significant association with persistent mastalgia were younger age and use of radiotherapy. There was no association between persistent pain and type of breast surgery (breast-conserving surgery vs. simple mastectomy vs. modified radical mastectomy). In addition, this subset of patients with chronic breast pain was found to have higher rates of depression and persistent worry about their breast pain signifying a relapse of cancer.

Pathophysiology of Mastalgia

Pathogenesis and Etiology

Epithelial and stromal activity, as well as regression, constantly occur within the breast. Fibrosis, adenosis, and lymphoid infiltration, commonly used to characterize mastalgia, cannot be correlated with clinical episodes. Watt-Boolsen and colleagues found no histologic differences between women with cyclic and noncyclic mastalgia and asymptomatic patients. Jorgensen and Watt-Boolsen reported fibrocystic changes in 100% of 41 women with breast pain who underwent breast biopsy. Although a higher incidence of fibrocystic changes was seen in this cohort than in asymptomatic controls, the total incidence of breast abnormalities did not differ between groups. Attempts to demonstrate edema as the main cause of cyclic pain and nodularity have been unsuccessful. Cysts that commonly occur with ANDI and mastalgia are secondary to changes of involution, periductal inflammation, and fibrosis, which may narrow the ducts distally and cause proximal dilation.

Endocrine Influences

The natural history of mastalgia is clearly linked to the reproductive cycle, with onset at the age of menarche, a linear increase in prevalence up to age 50, and cessation of symptoms for many women at menopause. In a prospective study of reproductive factors associated with mastalgia, Gateley and colleagues reported that women with cyclic mastalgia were more likely to be premenopausal, nulliparous, or to have been a young age when they had their first child. However, theories of the exact hormonal events, including progesterone deficiency, excess estrogen, changes in the progestin/estrogen ratio, differences in receptor sensitivity, disparate follicle-stimulating hormone (FSH) and luteinizing hormone (LH) secretion, low androgen levels, and high prolactin (PRL) levels, have been difficult to prove or have not abated with hormone therapy.

Under normal circumstances, PRL exerts structural growth and secretory differentiation, mammary immune system development, and initiation and maintenance of milk secretion. PRL secretion is episodic and shows circadian rhythm, with clustering of more intense episodes after midnight. In addition, PRL secretion has menstrual and seasonal variations. These variations may, to some extent, account for the discrepancies in available reports. Mastalgia may be related to an upward shift in the circadian PRL profile, a possible downward shift in menstrual profiles, and loss of seasonal variations. Patients with mastalgia also show a heightened PRL secretion in response to thyrotropin-releasing hormone (TRH) antidopaminergic drugs ( Fig. 14.1 ). In addition, stress can cause a rise in PRL response.

Fig. 14.1, Suggested theories of causation of breast pain.

Disturbances in the pituitary-ovarian steroid axis have long been associated with breast pain (see Fig. 14.1 ). However, numerous studies have not shown differences in estrogen and progesterone between asymptomatic controls and patients with mastalgia. Available reports have measured estrogen over various time courses, from single midluteal phase samples to daily for an entire cycle. Clearly, circadian, menstrual, seasonal, or episodic changes could have been overlooked. More importantly, normal breast function is a balance between estrogen and progesterone, which is a part of the neuroendocrine control exerted by the hypothalamic-pituitary-gonadal axis (see Fig. 14.1 ). The theory of an inadequate luteal phase defect has never been confirmed. Three studies have demonstrated a significant decrease in luteal phase progesterone in women with mastalgia versus pain-free control subjects; however, four other comparable studies have not confirmed these results. Nevertheless, an estrogen-progesterone imbalance could affect PRL secretion. An impairment of the normal ability to counteract estrogen-induced PRL release by increasing the central dopaminergic tone has been suggested as a cause of mastalgia.

Nonendocrine Influences

Caffeine intake was found to be related to mastalgia with statistical significance. In a series of 874 cases by Ader and colleagues, it was reported that both increased caffeine consumption and smoking were correlated with mastalgia. Serum studies in animals demonstrate that caffeine intake can increase PRL, insulin, and corticosterone and can decrease thyroid-stimulating hormone, free triiodothyronine, and thyroxine. Minton and colleagues originally hypothesized that methylxanthines, either by inhibiting phosphodiesterase and breakdown of cyclic adenosine monophosphate (cAMP) or by increasing catecholamine release, increase cAMP, leading to cellular proliferation in the breast (see Fig. 14.1 ). Tissue from patients with breast disease showed unchanged phosphodiesterase activity but appeared to have increased adenylate cyclase levels and increased responsiveness to the biochemical-stimulating effects of methylxanthines. Caffeine itself has no direct effect on cAMP, but catecholamines can increase cAMP. Studies in Minton’s laboratory have shown increased release of circulating catecholamines in response to caffeine consumption (see Fig. 14.1 ). Indeed, studies by Minton and Abou-Issa have shown “catecholamine supersensitivity” in patients with ANDI. There were significantly higher levels of beta-adrenergic receptors in symptomatic patients than in asymptomatic controls. The increased activity and sensitivity of the beta-adrenergic–adenylate cyclase system in symptomatic patients suggest a genetic predisposition for ANDI that is stimulated by the biochemical or hormonal effects of methylxanthines. Moreover, Butler and colleagues have been able to categorize patients genetically into fast and slow acetylators based on their caffeine metabolism. Like the methylxanthines, a common biochemical effect of nicotine, tyramine, and physical and emotional stress is enhancement of catecholamine release and an increase of circulating catecholamines (see Fig. 14.1 ). Arsiriy showed that women with mastalgia and ANDI had significantly higher levels of urinary catecholamines than did asymptomatic controls. Studies have shown increased serum epinephrine and norepinephrine and decreased baseline dopamine levels in patients with cyclic, as well as noncyclic, mastalgia. The increase or stimulation of adenylate cyclase activity in breast tissue appears to be an important step for triggering the intracellular cAMP-mediated events leading to symptomatic ANDI. Randomized studies on smoking, tyramine, or stress reduction have not been performed.

The theory that fat increases endogenous hormone levels, and thus breast pain, has led to the performance of dietary fat-restriction studies. In these studies, women with breast pain show lower levels of plasma essential fatty acid gamma-linolenic acid than do asymptomatic controls. It has been hypothesized that essential fatty acid deficiencies may affect the functioning of the cell membrane receptors of the breast by producing a supersensitive state. High levels of saturated fats inhibit the rate-limiting delta-6 desaturation step between linoleic acid and gamma-linolenic acid. Catecholamines, diabetes, glucocorticoids, viral infections, and high cholesterol levels likewise limit this step. With both estrogen and progesterone receptors, a supersensitive state can be produced with a higher ratio of saturated to unsaturated fatty acids. Administration of essential fatty acids in the form of evening primrose oil (EPO, 9% gamma-linolenic acid) bypasses the delta-6 desaturation step, leading to a gradual reduction in the proportions of the saturated fatty acids and diminishing the abnormal sensitivity of the breast tissue.

Anatomic and extrinsic factors may also contribute to the development of breast pain. Scurr and colleagues found breast pain to be related to cup size but not underband size. Women reported increased pain with participation in sports and activities exacerbated by ill-fitting and nonsupportive bras; however, overall breast pain was more common in women with lower activity levels. In a survey conducted in the female runners of the 2012 London marathon, 75% reported bra fit issues, most commonly chaffing and shoulder strap discomfort, suggesting that poor bra fit may be a factor in activity-related breast pain.

Furthermore, mastalgia is more prevalent among overweight and obese patients. Patients with body mass index (BMI) greater than 30 experienced mastalgia 1.7 times more frequently than women with BMI less than 30. Large and sagging breasts can stretch Cooper’s ligaments and cause breast pain. Mastalgia complaints are frequently noted in patients with macromastia.

Management of Mastalgia

As might be anticipated, there is a long list of suggested modalities for the treatment of a ubiquitous entity whose cause is unknown and whose relationship to fibrocystic breast disease and cancer is poorly understood. Breast pain may resolve spontaneously, and 19% of patients have marked responses to placebo therapy. Therefore double-blind placebo-controlled trials are required to prove the effectiveness of drugs in the treatment of mastalgia. Gamma-linolenic acid, bromocriptine, danazol, LH-releasing hormone (LHRH) agonists, molecular iodine, and tamoxifen have all been shown by such trials to be of use in the treatment of breast pain. The safety and efficacy of these therapies, as well as less proven therapies, are discussed in the next section ( Table 14.2 ).

Table 14.2

Effectiveness of Interventions for Mastalgia

	Mastalgia
Drug	Cyclical	Noncyclical	Combined	Side Effects
Methylxanthines	—	—	83%	None
Dietary fat reduction	90%	73%	83%	None
Evening primrose oil	58%	38%	—	4%
Molecular iodine	—	—	65%	11%
Danazol	92%	64%	—	30%
Gestrinone	—	—	55%	None
LHRH agonist	—	—	67%	37%
Thyroid replacement	—	—	73%	None
Analgesics	—	—	92%	None
Tamoxifen	90%	56%	—	65% ^a

LHRH , Luteinizing hormone–releasing hormone.

a Regimen is 20 mg of tamoxifen. On 10 mg, side effects and efficacy are lower.

Nutritional Therapy

Nutritional factors have been less well documented than other modalities in the cause and treatment of breast pain. Although they are the least expensive and least prone to side effects, dietary changes are often the most difficult to institute in the noncompliant patient.

Methylxanthines

Chemicals classified as methylxanthines include caffeine, theophylline, and theobromine. These substances are found in coffee, tea, chocolate, and cola beverages, as well as in many respiratory medications and stimulants. Minton and colleagues reported complete disappearance of all palpable nodules, pain, tenderness, and nipple discharge 1 to 6 months after eliminating methylxanthines from the diet of 13 of 20 women (65%). In a subsequent clinical trial involving 87 women, complete resolution was seen in 82.5%, with significant improvement in 15% of women abstaining from methylxanthines. Resumption of methylxanthines was associated with recurrence of symptoms in this cohort. These data are supported by nonrandomized studies, including retrospective data from 90 pairs of twins in which the twin with breast pain was found to be more likely to consume more coffee than the unaffected twin. Ernster and colleagues randomized 82 of 158 women to abstain from methylxanthine and 76 women to no dietary instruction. Differences in clinically palpable breast findings were significantly less in the caffeine-abstaining group, but absolute changes were minor. Bullough and colleagues studied daily methylxanthine ingestion from drug and dietary sources and found that both breast pain and fibrocystic disease are positively correlated with caffeine and with total methylxanthine ingestion. Minton reported the evaluation of 315 patients with ANDI for a mean of 3 years (range, 1–11 years), demonstrating improvement off caffeine and return of symptoms with resumption of caffeine.

Other case-controlled studies, however, have not confirmed these clinical findings. A study of an age- and race-matched cohort of approximately 3000 women who were a part of the Breast Cancer Detection Demonstration Project demonstrated no association between methylxanthine consumption and breast tenderness in women with fibrocystic disease or in controls. In a single-blind clinical trial of 56 women randomized to a control (no dietary restrictions), a placebo (cholesterol-free diet), and an experimental group (caffeine-free diet) for 4 months, Allen and Froberg showed that caffeine restriction did not lessen breast pain or tenderness. Another factor is the significant difference in the length of withdrawal of caffeine seen between positive and negative studies. Minton’s work has been criticized for lack of control subjects and blinding, as well as for the general instability of findings in patients with mastalgia. An unflawed, large-scale, prospective long-term study that would count methylxanthines from all sources and use reliable dependent variables to assess pain, either to prove or disprove the value of methylxanthine withdrawal, has yet to be performed. Until then, clinicians may want to suggest a methylxanthine-restricted diet, especially in light of its no-cost, no–side-effect status and the other unwanted health consequences of caffeine.

Dietary

As with breast cancer, mastalgia is less common in the global East where diets are notably lower in fat. Reduction of dietary fat intake (to <15% of total calories for 6 months) significantly improves cyclic breast tenderness and swelling. In one study, Sharma and colleagues demonstrated significant elevations in high-density lipoprotein cholesterol and the ratio of high-density lipoprotein cholesterol to low-density lipoproteins, as well as a decrease in the ratio of total cholesterol to high-density lipoprotein cholesterol, in 32 cyclic and 25 noncyclic mastalgia patients. Response to a low-fat dietary regimen was significant only in the cyclic mastalgia group, suggesting that cyclic mastalgia may be from cyclic aberrations in lipid metabolism and that dietary management may need to be pursued. A good or partial response was seen in 19 of 21 of the cyclic and 11 of 15 of the noncyclic patients. It is unclear what would lead to such a lipid profile abnormality—whether excessive intake, a genetic predisposition, or both. Nevertheless, dietary manipulation of this kind is difficult to achieve, is difficult to monitor, and requires a high degree of compliance.

Furthermore, losing weight can have a positive effect on mastalgia, as obesity is an independent risk for mastalgia. In one cross-sectional study of 752 women, a BMI over 30 and weight gain over the last 5 years were deemed to be risk factors for mastalgia. Therefore it was concluded that weight management can be an effective approach to mastalgia prevention. A study performed by Comcali and colleagues revealed that women who had lost weight and returned to an ideal body weight had mild to no complaints of mastalgia.

Alcohol and tobacco

There are mixed findings regarding alcohol and cigarette use and its relationship to mastalgia. In a study by Comcali, consumption of alcohol, at least once per week, increased mastalgia complaints by 54-fold. Furthermore, those that smoked more than 10 cigarettes per day were 4.1 times more likely to complain of mastalgia. However, in a case-control study performed by Idiz and colleagues, smoking and alcohol consumption were not different between the mastalgia and control groups.

Evening primrose oil, omega-3 fatty acids, and vitamins

Studies have shown that women with severe cyclic mastalgia have abnormal blood levels of some essential fatty acids, which have been implicated in the control of PRL secretion and steroid hormone receptor alterations. Early clinical experience with EPO, a source of gamma-linolenic acid, produced a 58% response rate with cyclic mastalgia and a 38% response rate with noncyclic mastalgia. Symptoms of pain and nodularity were significantly improved with EPO (3 g/day) in a placebo-controlled trial after 4 months, and treatment was associated with an elevation of essential fatty acids toward normal levels. A recent small pilot study of 41 patients randomized to receive EPO (3 g/day), vitamin E (1200 IU/day), or both found an improvement in worst pain in all three treatment groups but no difference with placebo ( P = 0.093) in intent-to-treat analysis. A recent study by Balci and colleagues found a statistically significant therapeutic efficacy of EPO on mastalgia compared with paracetamol. Several factors were found to influence the efficacy of EPO, including iron-deficiency anemia and hypothyroidism. It was found that replacement of iron or thyroid hormone efficiently treated mastalgia in patients that did not respond to EPO treatment.

Two more randomized controlled trials have not supported or contradicted this evidence of the efficacy of EPO in the treatment of mastalgia. In a large multicenter trial, Goyal and colleagues evaluated mastalgia in 555 women and compared EPO plus antioxidants, EPO plus placebo antioxidants, antioxidants plus placebo EPO, and placebo antioxidants and placebo EPO. After 4 months, the investigators found no difference in recorded pain scores between women taking EPO plus vitamins versus placebo plus vitamins (15.2 vs. 14.9; P = 0.3). Similarly, Blommers and colleagues found no significant difference between EPO and placebo in the frequency or severity of pain at 6 months. In this trial, 120 women were studied in four comparison groups: EPO plus placebo oil, fish oil plus placebo oil, fish oil plus EPO, and two placebo oils alone. Furthermore, a large meta-analysis performed by Srivastava and colleagues reviewing the data from all randomized controlled trials using EPO revealed no significant beneficial effect of EPO over placebo. This new evidence, in part, questions or refutes the utility of EPO as a first-line agent in the treatment of mastalgia, and the United Kingdom has withdrawn the prescription license for EPO because of its lack of efficacy.

Flaxseed oil, a rich source of alpha-linolenic acid (ALA), has also been shown to reduce breast pain, by having selective estrogen receptor modulator (SERM) properties. ALA has antiinflammatory properties and reduces inflammatory cytokines, thereby reducing oxidative stress. An article by Kaithwas and colleagues describes how ALA is transformed to eicosapentaenoic acid and can inhibit arachidonic acid metabolism. This has antibradykinin and antihistamine effects. In a small randomized controlled trial, women receiving 25 g flaxseed daily had reduced cyclical breast pain at both 1- and 2-month time points compared with placebo. In a more recent study performed by Adibmoghaddam and colleagues, flaxseed supplementation was compared with EPO and vitamin E to assess the effectiveness of these agents in reduction of breast pain. There was only a significant reduction in breast pain in the flaxseed group ( P = 0.006). Effectiveness was attributed to flaxseed serving as the richest source of omega-3 essential fatty acids as it contains phytoestrogens, lignans, and antioxidants. Flaxseed also has few side effects and can reduce symptoms of periodic pain for a longer period than the other agents.

Vitamin E oil works in a similar fashion to flaxseed oil to reduce inflammation and pain. Vitamin E has antioxidant effects that decrease the production of prostaglandins. This inhibits the release of arachidonic acid. Abrams reported a favorable response to vitamin E in an uncontrolled trial in 1965. In a small, prospective, double-blind crossover study of the efficacy of vitamin E or placebo, 10 of 12 patients receiving 300 IU/day and 22 of 26 patients receiving 600 IU/day showed improvement after 4 weeks of taking vitamin E. Serum levels of dehydroepiandrosterone, but not estrogen or progesterone, were significantly higher in the responders to the drug before and normalized after administration of vitamin E. Meyer and colleagues conducted a double-blind, placebo-controlled crossover trial that randomized 105 women to receive either vitamin E (600 IU/day) for 3 months or placebo. Although 37% reported improvement while taking vitamin E, versus 19% reporting improvement with placebo, this was not statistically significant. Parsay and colleagues, however, showed a significant improvement in cyclic mastalgia in women treated with vitamin E (400 IU/day) versus placebo in a randomized double-blind study of 150 women at both 2- and 4-month time intervals. In contrast, double-blind placebo-controlled trials by London and colleagues (128 patients receiving 150, 300, and 600 IU vitamin E for 2 months) and Ernster and colleagues (73 patients receiving 600 IU for 2 months) reported no benefits from vitamin E. In a 2019 meta-analysis by Hajizadeh and colleagues, vitamin E was found to be a low side-effect therapy with the ability to reduce both the severity and duration of mastalgia symptoms compared with placebo therapies, which have been found to mainly reduce pain severity. Although several older studies did not show statistically significant improvement of mastalgia with vitamin E use, the more recent consensus supports the use of vitamin E as a safe and effective method of treating mastalgia.

Endocrine Therapy

Although it is difficult to prove, hormonal factors clearly play a role in the cause of cyclic mastalgia. This is evidenced by the fact that the condition manifests itself primarily during the ovulatory years, with symptoms that fluctuate during the course of the menstrual cycle, intensifying premenstrually and subsiding with menses.

Androgens

Testosterone

One of the earliest effective hormonal treatments for mastalgia was testosterone injections. Its use has been limited by its adverse side effects. However, results from a placebo-controlled trial using 40 mg twice daily of the undecanoate oral form of testosterone demonstrated a reduction in mastalgia pain scores of 50%, with acceptable tolerance.

Danazol

Danazol is an attenuated androgen and the 2,3-isoxazol derivative of 17α-ethinyl testosterone (ethisterone). Danazol competitively inhibits estrogen and progesterone receptors in the breast, hypothalamus, and pituitary ; inhibits multiple enzymes of ovarian steroidogenesis ; inhibits the midcycle surge of LH in premenopausal women; and reduces gonadotropin levels in postmenopausal women. The precise mechanism of danazol in reducing breast pain is unknown. It is the only medication approved by the US Food and Drug Administration (FDA) for the treatment of mastalgia.

In initial studies, a double-blind crossover trial comparing two dosages of danazol (200 vs. 400 mg/day) in 21 patients with mastalgia demonstrated significant decreases in pain and nodularity at both dosages. Onset of response and side effects were higher with the higher dosage. Of the participants, 30% had amenorrhea and weight gain. There was significant reduction in mean pain scores and mammographic density using danazol in a randomized trial with daily treatments of 200 or 400 mg of danazol for 6 months. Patients relapsed more quickly (9.2 vs. 12.2 months) and to a greater extent (67% vs. 52%) in women taking 200 versus 400 mg of danazol. Gateley and colleagues found a clinically useful response to danazol (200 mg/day) in 92% of 324 patients with cyclical mastalgia and 64% of 90 patients with noncyclical mastalgia with 30% experiencing adverse events (mainly weight gain and menstrual irregularity) and 43 patients having to stop treatment despite 19 having an effective response. Because the side effects of danazol are dose related, Harrison and colleagues and Sutton and O’Malley developed low-dose regimens. Patients responding to a dosage of 200 mg/day of danazol after 2 months were given a dosage of 100 mg/day for 2 months and then 100 mg every other day or 100 mg daily only during the second half of the menstrual cycle. If previous reductions were well tolerated, the danazol was discontinued. Symptoms were controlled without side effects at a total average monthly dose of 700 mg. Of 20 women, 13 (65%) of whom had experienced previous side effects, none reported side effects while taking this low dose. Some relief of pain was seen in all women, with a complete response maintained in 55%. Other reported side effects of danazol include muscle cramps, acne, oily hair, hot flashes, nervousness, hirsutism, voice change, fluid retention, increased libido, depression, headaches, and dyspareunia, which usually resolve after discontinuation of treatment. The drug is contraindicated in women with a history of thromboembolic disease. For women of childbearing age, adequate nonhormonal contraception is essential.

Recommendations for the administration of danazol are 100 mg twice daily for 2 months while the patient keeps a breast pain record. If no response or an incomplete response is obtained, the dose may be increased to 200 mg twice daily. If there is still no response, another drug should be tried. Therapy should not continue longer than 6 months (because side effects may develop), and the drug should be tapered, as described by Harrison and colleagues and Sutton and O’Malley.

Hormonal contraceptives

In a study by Karimian and colleagues, correction of menstrual irregularity was found to provide significant breast pain relief in women with cyclic mastalgia. Initially during the study, there was no significant improvement in mastalgia symptoms; however, by the end of the study, there was a significant improvement in mild and severe mastalgia in the case group (low-dose oral contraceptive pill in addition to 100 mg vitamin E) compared with the control group, who only received 100 mg vitamin E ( P = 0.003 and P = 0.045, respectively). This study suggested that correcting menstrual irregularity should serve as a first-line treatment in women with mastalgia.

Others

Luteinizing hormone–releasing hormone agonists

The mechanisms of LHRH analogs are thought to be their antigonadotropic action and direct inhibition of ovarian steroidogenesis, which almost completely induce ovarian ablation, resulting in extremely low levels of the ovarian hormones estradiol, progesterone, androgens, and PRL. In a nonrandomized trial, Monosonego and colleagues gave intramuscular LHRH agonist (3.75 mg as a monthly depot) to 66 patients during a 3- to 6-month period. A complete response was observed in 44% of the patients treated with an LHRH agonist alone, and a partial response was seen in 45%. Monthly injections of the LHRH analog goserelin resulted in significantly diminished pain in 67% of patients with either cyclic or noncyclic mastalgia in a randomized multicenter study of 147 premenopausal women. Side effects, which included vaginal dryness, hot flashes, decreased libido, oily skin or hair, and decreased breast size, were seen more frequently in patients receiving goserelin (27/73 patients) than sham (4/74 patients). Significantly, treatment with an LHRH agonist induced remarkable loss of trabecular bone. For this reason, only short courses of LHRH analogs should be administered and only for acute and severe cases of mastalgia.

Thyroid hormone

Data from in vitro studies have suggested that thyroid hormones may antagonize the effects of estrogen at the pituitary receptor levels of lactotrophs, such as TRH, although there is no conclusive support for this. Relative estrogen dominance is suggested as a cause for the increase in PRL responsiveness to TRH in patients with mastalgia.

Kumar and colleagues found a generalized abnormality of the hypothalamic-pituitary axis in 17 patients with cyclic mastalgia compared with 11 controls by using a combined TRH and gonadotropin-releasing hormone test. The release of PRL, LH, and FSH was significantly greater in patients with cyclic mastalgia than in controls, although estrogen and progesterone levels were normal. Bhargav and colleagues studied 201 women with BBD, none of whom had previously suspected hypothyroidism. The prevalence of hypothyroidism was 23.2%, and relief of BBD symptoms was attained in 83% of patients with hypothyroidism with thyroid replacement alone. A large, randomized, placebo-controlled trial of levothyroxine is needed before any recommendation is made for its use as a standard treatment.

Nonendocrine Therapy

Bromocriptine

Results of recent studies point toward a PRL secretory hypersensitivity for estradiol in patients with cyclic mastalgia (see Fig. 14.1 ). Watt-Boolsen and colleagues studied 20 women with cyclic mastalgia and compared them with 10 women who were asymptomatic. Basal serum PRL levels were significantly elevated, although within the normal range, in the mastalgia group versus controls. Cole and colleagues have demonstrated that PRL is involved in the regulation of water and electrolyte balance in the nonlactating breast. An increase in serum PRL levels could possibly cause an influx of water and electrolytes in the breast, thus increasing tension and causing pain. However, in women with true hyperprolactinemia, levels of mammotrophic hormones are entirely different because ovarian steroid levels are suppressed. Bromocriptine is an ergot alkaloid that acts as a dopaminergic agonist on the hypothalamic-pituitary axis. One result of this action is suppression of PRL secretion.

Mansel and colleagues reported a double-blind crossover study using bromocriptine in a group of patients with mastalgia. Lowered PRL levels associated with a significant clinical response were seen in patients with cyclic breast pain but not in those with noncyclic breast pain. In a double-blind controlled trial of danazol and bromocriptine, Hinton and colleagues reported a clinical response with bromocriptine in two-thirds of patients with cyclic pain but no response in patients with noncyclic pain. In contrast, Pye and colleagues reported a minimal response rate of 20% with bromocriptine in patients with noncyclic mastalgia versus 47% in those with cyclic mastalgia. The European Multi-Center Trial of bromocriptine in cyclic mastalgia confirmed the efficacy of bromocriptine. Side effects occurred in 45% of patients and were severe enough to warrant discontinuation of therapy in 11%. Side effects were reduced by an incremental buildup of doses over 2 weeks. However, reports of serious side effects of bromocriptine prescribed for lactation cessation, including seizures (63), strokes (31), and deaths (9), have resulted in its removal from the indication list of bromocriptine by the FDA. Despite its apparent effectiveness, because of the seriousness and frequency of the reported side effects, we do not recommend bromocriptine for use in mastalgia.

Cabergoline, another long-lasting, potent dopamine, has been demonstrated to be as effective as bromocriptine with fewer side effects. In a multicenter open-label study of 140 women with cyclic mastalgia randomized to receive bromocriptine (5 mg/day during the second half of the menstrual cycle) or cabergoline (0.5 mg/week during the second half of the menstrual cycle), 66.6% of women receiving bromocriptine and 68.4% of women receiving cabergoline had a positive response. Side effects were, however, much lower in the cabergoline group, with less frequent vomiting (4.5% vs. 28%), nausea (20.9% vs. 39%), and headache (6% vs. 23%) when comparing cabergoline with bromocriptine. In this small study, the serious side effects observed with bromocriptine (i.e., seizure, stroke, or death) did not occur.

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