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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 9 4428-4433
Copyright © 2004 by The Endocrine Society

Safety and Efficacy of Anastrozole for the Treatment of Pubertal Gynecomastia: A Randomized, Double-Blind, Placebo-Controlled Trial

Paul V. Plourde, Edward O. Reiter, Hann-Chang Jou, Paul E. Desrochers, Stephen D. Rubin, Barry B. Bercu, Frank B. Diamond, Jr. and Philippe F. Backeljauw Members of the AstraZeneca Gynecomastia Study

AstraZeneca Pharmaceuticals LP (P.V.P., H.-C.J., P.E.D., S.D.R.), Wilmington, Delaware 19850; Baystate Medical Center-Children’s Hospital (E.O.R.), Springfield, Massachusetts 01199; University of South Florida (B.B.B., F.B.D.), St. Petersburg, Florida 33701; and Cincinnati Children’s Hospital Medical Center (P.F.B.), Cincinnati, Ohio 45229

Address all correspondence and requests for reprints to: Dr. Paul V. Plourde, AstraZeneca Pharmaceuticals LP, Chesapeake 2B-126, 1800 Concord Pike, P.O. Box 15437, Wilmington, Delaware 19850-5437. E-mail: paul.plourde{at}astrazeneca.com.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Pubertal gynecomastia is thought to result from transient imbalances between estrogen and androgen concentrations. Anastrozole (ARIMIDEX), a potent and selective aromatase inhibitor, decreases estrogen and increases testosterone concentrations in pubertal boys. The safety and efficacy of anastrozole for the treatment of pubertal gynecomastia were evaluated. In a randomized, double-blind, placebo-controlled study of 80 boys, aged 11–18 yr, with pubertal gynecomastia that had not reduced over a 3-month interval, subjects received either anastrozole (1 mg) or placebo once daily for 6 months. A response was defined as a 50% or greater reduction in the calculated volume of both breasts combined using ultrasonography measurements. A comparison of response rates was performed using logistic regression analysis. Secondary end points included changes in serum hormone concentrations. The percentage of patients with a response was 38.5% for the anastrozole group and 31.4% for the placebo group (odds ratio, 1.513; 95% confidence interval, 0.496–4.844; P = 0.47). At 6 months, the median percent change in the testosterone/estradiol ratio was 166% for the anastrozole group and 39% for the placebo group. Anastrozole treatment was well tolerated. In patients with pubertal gynecomastia, no significant difference in the percentage of patients with a 50% or greater reduction in total breast volume, as calculated from ultrasonography measurements, was demonstrated between the anastrozole and placebo groups.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
GYNECOMASTIA, WHICH OCCURS transiently in 30–60% of pubertal boys, is thought in most cases to result from an imbalance between the stimulatory effects of estrogens and the inhibitory effects of androgens (1, 2). The mechanism of this imbalance may be multifactorial (1, 3). Histologically, gynecomastia can progress from a florid type, characterized by ductal proliferation and the formation of vascularized connective tissue stroma (usually <6-month duration) to a chronic fibrous type with dilated ducts and increased stromal hyalinization (usually ≥1-yr duration) (4, 5, 6). Although most cases of pubertal gynecomastia resolve spontaneously, up to 25% of cases may persist for 2 yr or longer (7). Pubertal gynecomastia can interfere with normal daily activities and be associated with marked breast pain or tenderness that may necessitate pharmacological or surgical treatment.

No pharmacological agents for the treatment of gynecomastia have been approved by the FDA. However, various hormonal therapies (i.e. antiestrogens, androgens, and weak aromatase inhibitors) have been evaluated in patients with gynecomastia of various etiologies (8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32). The results of many of these studies have been difficult to interpret because of the small number of patients treated and the absence of placebo-treated controls. Of the four studies with a randomized, placebo-controlled design (14, 18, 24, 31), none has evaluated patients with pubertal gynecomastia. However, in two randomized, placebo-controlled, cross-over trials of adults with gynecomastia, treatment with the selective estrogen receptor modulator tamoxifen (10 mg twice daily) reduced breast pain and breast tissue size compared with placebo treatment without adverse effects (14, 18).

In men, approximately 80% of circulating estrogens are produced in extraglandular tissues (e.g. adipose, muscle, skin, and bone) by the enzyme aromatase using the substrates testosterone and androstenedione (33). Anastrozole (ARIMIDEX, AstraZeneca Pharmaceuticals LP, Wilmington, DE), a potent and selective aromatase inhibitor, decreased serum estradiol concentrations approximately 50%, increased serum testosterone concentrations approximately 60%, and was well tolerated in pubertal boys (34). We hypothesized that the increase in the testosterone/estradiol (T/E) ratio with anastrozole treatment might ameliorate pubertal gynecomastia. The goals of the present study were to determine whether anastrozole (1 mg) was more effective than placebo in the treatment of gynecomastia in pubertal boys, as assessed by changes in breast tissue size and breast pain symptoms, and to assess the safety and tolerability of anastrozole in this patient population.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
Patients

Males, aged 11–18 yr, with pubertal gynecomastia (i.e. one breast measuring ≥3 cm in diameter that had not decreased in diameter by 0.5 cm during 3 months of observation) were eligible for inclusion in the study. Other inclusion criteria were normal kidney, liver, and thyroid function; no evidence of hormone-producing tumor, hypogonadism, or androgen resistance; written informed consent provided by patients and/or their parents or guardians; and Tanner staging conducted at pretreatment visit. Patients taking medications known to cause gynecomastia within the previous 6 months were excluded from the study.

Study design

In a double-blind, placebo-controlled, multicenter study, eligible patients were randomized sequentially to receive either anastrozole (1 mg) or matching placebo once daily for 6 months. The study was performed in accordance with the ethical principles in the Declaration of Helsinki and applicable regulatory requirements. An institutional review board at each of the 24 study sites approved the study.

Assessments

Efficacy data were analyzed from all randomized patients (including protocol violators) who took at least one dose of treatment and had at least one data point after dosing (intent to treat population). The primary efficacy variable was the response rate after 6 months of treatment [i.e. proportion of patients achieving a ≥50% reduction in the calculated volume of gynecomastia (both breasts combined), as measured by ultrasound]. Measurements of the transverse, sagittal, and anteroposterior diameters of each breast were determined using high resolution ultrasound (10 MHz or equivalent transducers) at visit 1 (randomization) and after 6 months of treatment (or withdrawal from the study). The anteroposterior diameter measurement was defined as the distance from the areola to the anterior chest wall (posterior breast), with no significant pressure applied with the transducer during the measurement. The total breast tissue volume (of both breasts combined) was calculated from the product of the three diameters. A consulting radiologist reviewed the ultrasound images of 16 randomly selected patients from among the 24 study sites to compare local readings with the central measurements. No major discrepancies were observed between the measurements provided by radiologists at the study sites and those provided by the consulting radiologist.

Secondary efficacy variables were the actual change and percent change in the calculated volume of gynecomastia, the proportion of patients with a complete regression of gynecomastia, breast pain (tenderness) response in symptomatic patients (i.e. patients who reported breast pain/tenderness at baseline visit), and changes in serum concentrations of testosterone, estradiol, and gonadotropins and in the T/E ratio after 6 months of treatment. All blood samples were analyzed at a central laboratory (SmithKline Beecham Clinical Laboratories/Quest Diagnostics, Van Nuys, CA), with the exception of two sites that used local laboratories. The sensitivity of the estradiol assay used at the central laboratory and one of the local laboratories was 10.0 pg/ml (36.7 pmol/liter); the sensitivity of the estradiol assay used at the other local laboratory was 5.0 pg/ml (18.4 pmol/liter; two patients). Adverse events were recorded monthly, at withdrawal, and at 30 d of follow-up. A complete blood count and sequential multiple analyzer test (i.e. liver function enzymes, creatinine, and blood urea nitrogen) were conducted at the pretreatment visit; the blood concentration of human chorionic gonadotropin was measured at the baseline visit, and serum hormone concentrations were measured at the baseline visit and after 3 and 6 months of treatment or at the final visit. A physical examination was performed at the pretreatment visit, the baseline visit, and after 3 and 6 months of treatment or at the final visit.

Statistical analysis

For estimating the required sample size, response rates of 85% for the anastrozole group and 40% for the placebo group were assumed. The assumed response rate for the anastrozole group was based on a complete regression of pubertal gynecomastia in 12 of 14 patients (86%) treated for 2.4 months with tamoxifen (16). The assumed response rate for the placebo group was based on the spontaneous resolution of pubertal gynecomastia in 38% of patients within 6 months (35). Using the normal approximation to the binomial distribution and assuming that approximately 20% of patients would withdraw from the study or have missing data, a sample size of 30 in each treatment group was estimated to be required to provide more than 80% power at the 5% level of significance to detect a difference of 45% between the two treatment groups.

The response rates of the two treatment groups were compared using a logistic regression model, with adjustment for the following covariates at baseline: body mass index (BMI), duration of gynecomastia, total breast volume (both breasts combined), and hormone levels (testosterone, estradiol, FSH, LH, and SHBG). Missing efficacy data were filled in using the last observation carried forward method. Data for secondary efficacy endpoints and safety outcomes were analyzed descriptively.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
Patient population

The flow of patients through the study is shown in Fig. 1Go. Of 82 patients randomized to treatment (anastrozole, n = 44; placebo, n = 38), one patient in each treatment group did not take at least one dose of treatment. Four patients in the anastrozole group and two patients in the placebo group had no efficacy end-point data after dosing; hence, these patients were excluded from the efficacy group (i.e. intent to treat population for efficacy: anastrozole, n = 39; placebo, n = 35).



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  		FIG. 1. Patient flow through the study.

 
At baseline, the two treatment groups were generally well balanced with respect to demographics, characteristics, and serum hormone concentrations (Tables 1Go and 2Go). The duration of gynecomastia was more than 1 yr in 91% of the patients. Fourteen of 39 patients (36%) in the anastrozole (1 mg) group and 12 of 35 patients (34%) in the placebo group had baseline serum estradiol concentrations that were at or below the lower limit of detection.


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  		TABLE 1. Baseline characteristics of boys with pubertal gynecomastia

 

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  		TABLE 2. Serum estradiol (E) and testosterone (T) concentrations at baseline and after 6 months of treatment

 
Efficacy assessments

No significant difference was observed between the two treatment groups in the percentage of patients with a 50% or greater reduction in total breast volume after 6 months of treatment [anastrozole, 38.5% (95% confidence interval [CI], 23.4–55.4%); placebo, 31.4% (95% CI, 16.9–49.3%); odds ratio, 1.513 (95% CI, 0.496–4.844); P = 0.47; Fig. 2Go]. The two treatment groups were generally similar with respect to the observed mean ± SD actual change in the calculated breast tissue volume (anastrozole, –130.3 ± 353.5 ml; placebo, –216.1 ± 565.8 ml) and percent change from baseline in the calculated breast tissue volume (anastrozole, –23.5% ± 66.1; placebo, –5.9% ± 118.3) after 6 months of treatment with anastrozole or placebo. One patient (2.6%) in the anastrozole treatment group and no patient in the placebo treatment group had a complete regression of gynecomastia after 6 months of therapy. The number of patients reporting breast pain (tenderness) decreased from 11 at baseline to one after 6 months of treatment with anastrozole (1 mg) and from nine at baseline to zero after 6 months of treatment with placebo.



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  		FIG. 2. No significant difference was observed between the two treatment groups in the percentage of patients with a 50% or greater reduction in total breast volume after 6 months of treatment.

 
The median percent change in serum estradiol concentration was –20% for anastrozole and 0% for placebo; for serum testosterone, the median percent change was 87% for anastrozole and 4% for placebo (Table 2Go). The median percent change in FSH was 34% for anastrozole and –8% for placebo (Table 3Go). Twenty of 39 patients (51%) in the anastrozole group had serum estradiol concentrations at or below the lower limit of detection at 6 months (10 of whom had serum estradiol concentrations below the lower limit of detection of the assay at baseline) compared with seven of 35 patients (20%) in the placebo group (four of whom had serum estradiol concentrations below the lower limit of detection at baseline). After 6 months of treatment, the median percent change in the T/E ratio was 166% for anastrozole and 39% for placebo (Table 2Go). This marked difference confirmed the bioactivity of anastrozole (1 mg) in this patient population.


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  		TABLE 3. Serum FSH and LH concentrations at baseline and after 6 months of treatment

 
The treatment groups were generally well balanced in demographic and baseline characteristics, including baseline BMI. Statistical models (logistic regression and general linear model) did not find the prognostic factors specified in the protocol [including baseline BMI, duration of gynecomastia at baseline, baseline total breast volume (both breasts combined), baseline hormone levels (testosterone, estradiol, FSH, LH, and SHBG)] useful in explaining the response or change in breast volume. Furthermore, there was no correlation between these prognostic variables and either response or change in breast volume within each treatment group.

Safety assessments

Treatment with anastrozole (1 mg) was well tolerated. The nature and incidence of adverse events were similar in the anastrozole and the placebo groups. The most common adverse events were headache (anastrozole, 26%; placebo, 22%), pharyngitis (anastrozole, 19%; placebo, 30%), rhinitis (anastrozole, 14%; placebo, 14%), acne (anastrozole, 12%; placebo, 11%), and sinusitis (anastrozole, 9%; placebo, 11%). The incidence rates of rash (anastrozole, 9.3%; placebo, 0%) and flu syndrome (anastrozole, 7.0%; placebo, 0%) were higher in the anastrozole group, whereas the rates of increased cough (anastrozole, 0%; placebo, 8.1%), epistaxis (anastrozole, 0%; placebo, 5.4%), and reaction unevaluable (wisdom tooth extraction; anastrozole, 0%; placebo, 5.4%) were lower in the anastrozole group. The majority (>99%) of adverse events were mild to moderate in nature. Only one patient discontinued anastrozole treatment because of an adverse event (testicular enlargement). No serious adverse events were reported in either treatment group.


   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
Numerous physiological and pathological mechanisms can account for the estrogen-androgen imbalance that may cause gynecomastia (1, 36). The complexities of estrogen and androgen metabolism, together with the extraglandular formation of estrogens via the enzymatic aromatization of androgens, suggest that several factors may simultaneously contribute to this hormone imbalance. The results of several studies have suggested that aromatase dysregulation may play a role in some cases of gynecomastia (2). A recent study described an autosomal dominant mutation that affected the aromatase gene of three patients with severe prepubertal-onset gynecomastia (37). Aromatase activity in skin fibroblasts and adipose tissue samples from these patients was 11 to 24-fold higher than that in control subjects. Thus, aromatase inhibitors may be valuable therapeutic agents in certain subpopulations of patients with gynecomastia.

In the present study of pubertal boys with pubertal gynecomastia, no significant difference was observed in the proportion of patients who had a 50% or greater reduction in total breast tissue volume, as assessed by ultrasound, after 6 months of treatment with anastrozole (1 mg) or placebo. The actual mean change and the mean percent change from baseline in the calculated breast tissue volume after 6 months of treatment also were similar in the anastrozole (1 mg) and placebo groups. Furthermore, the number of patients with breast pain (tenderness) at 6 months was markedly reduced for both treatment groups. The difference between the two treatment groups in the median percent change in the T/E ratio reflected the pharmacodynamic activity of anastrozole (1 mg). Differences between the two treatment groups in the change in serum hormone concentrations were difficult to interpret because of the high degree of variability for all hormone concentrations assessed and the lack of sensitivity of the estradiol assay used. Treatment with anastrozole (1 mg) was well tolerated in this patient population. The nature and incidence of adverse events were similar in the anastrozole and placebo treatment groups.

Several limitations of the present study that may affect interpretation of the results deserve consideration. First, because of the limited number of placebo-controlled studies that have evaluated potential treatments for pubertal gynecomastia and the fact that pubertal gynecomastia often resolves spontaneously, estimation of the sample size necessary to observe a significant difference between active drug and placebo treatment groups is problematic. As a result, the present study may have been insufficiently powered. Second, there are no well established end points for assessing clinical benefit in patients with pubertal gynecomastia. The present study used a 50% or greater reduction in the calculated total breast tissue volume as the primary end point, whereas randomized controlled studies of adults with gynecomastia have used a change in palpable breast diameter or a decrease of 1 or more in Marshall-Tanner stage (14, 18). Third, there is no gold standard method for measuring changes in breast tissue size in patients with gynecomastia. Ultrasound determinations of the transverse, sagittal, and anteroposterior diameters of each breast were used in the present study to calculate a total breast tissue volume, whereas a single measurement of the palpable diameter, the longer of the horizontal or vertical palpable diameter, or the mean of the horizontal and vertical palpable diameters has been used in previous studies (10, 14, 21, 32). Ultrasound measurements of breast tissue volume in women with breast tumors have been reported to be more accurate than palpable diameter or mammography measurements (38, 39, 40, 41), but the accuracy of ultrasound measurements may decrease for tumors with a diameter greater than 20 mm and for those with an extensive intraductal component (42). The accuracy and reliability of these methods in patients with gynecomastia require further evaluation. The duration of gynecomastia in the patient population studied also may have affected the response rate observed. A conscious effort to include only those patients with stable or progressing pubertal gynecomastia resulted in a sample in which all patients had a disease duration of more than 6 months, and 91% had a disease duration of more than 1 yr. It has been suggested that pharmacological therapies would be expected to be most beneficial during the first 6 months of gynecomastia (i.e. during the florid stage of active proliferation) (2). Thus, both methodological issues and patient inclusion criteria may need to be reevaluated for future studies of pharmacological therapies for pubertal gynecomastia.

Although the estradiol assay used in the study lacked sensitivity, the marked increase in the serum T/E ratio strongly suggested the pharmacological activity of anastrozole in these patients with pubertal gynecomastia. The median percent change in serum estradiol concentration was –20% for anastrozole. The results of other studies using a very sensitive estradiol assay have indicated that anastrozole (1 mg) reduced serum estradiol concentrations by approximately 50% in both healthy adolescents and adult men (34). This would suggest that significant estrogen reduction did occur, but this reduction may not have been enough if gynecomastia tissue was ultrasensitive to small residual concentrations of estrogen.

Finally, pubertal gynecomastia may be a heterogeneous disease. In some patients, pubertal gynecomastia may not result from alterations in the T/E ratio, but, rather, from alterations in other signaling pathways. Alternatively, pubertal gynecomastia that was initially caused by an altered T/E ratio may become refractory to hormonal signaling with time. With either scenario, it may be possible that aromatase inhibitor therapy benefits a subset of patients not discernible within the current study.

In a randomized, placebo-controlled study, treatment with tamoxifen (20 mg daily) or anastrozole (1 mg daily) was evaluated for the prevention of bicalutamide-induced gynecomastia/breast pain, as assessed by physical examination, in 93 men with prostate cancer (43). Patients receiving tamoxifen had a significantly reduced risk of gynecomastia/breast pain after 3 months of treatment compared with those receiving placebo (relative risk, 0.35; 95% CI, 0.13–0.83; P < 0.0001), whereas the risk of gynecomastia/breast pain for patients receiving anastrozole was not significantly different from that of placebo-treated patients. These results together with the results of the present study and studies of tamoxifen therapy in patients with gynecomastia (14, 15, 17, 18, 19, 21) suggest that selective estrogen receptor modulators may be the pharmacological treatment of choice for most patients with gynecomastia.

In summary, in pubertal boys with gynecomastia, no significant difference in the percentage of patients with a 50% or greater reduction in total breast volume, as calculated from ultrasonography measurements, was demonstrated between those receiving anastrozole (1 mg) and those receiving placebo for 6 months. Treatment with anastrozole was well tolerated in this patient population. Additional studies of treatment with third-generation aromatase inhibitors in patients with earlier stages of gynecomastia are warranted.


   Acknowledgments
 
Patricia Leinen, Ph.D. (Tri-Med Communications, Media, PA), contributed to the preparation of the manuscript.


   Footnotes
 
This work was supported by a grant from AstraZeneca LP.

AstraZeneca Gynecomastia Study Investigators: Edward Reiter, M.D. (Springfield, MA); Philippe Backeljauw, M.D. (Cincinnati, OH); Samuel J. Casella, M.D. (Baltimore, MD); Barry Bercu, M.D., and Frank B. Diamond, M.D. (St. Petersburg, FL); Erica A. Eugster, M.D. (Indianapolis, IN); Larry Fox, M.D. (Jacksonville, FL); Paul B. Kaplowitz, M.D. (Richmond, VA); Michael S. Kappy, M.D., Ph.D. (Denver, CO); Peter A. Lee, M.D., Ph.D. (Hershey, PA); John W. Mace, M.D. (Loma Linda, CA); Thomas Moshang, Jr., M.D. (Philadelphia, PA); David Schwartz, M.D., and Wayne Moore, M.D., Ph.D. (Kansas City, MO); Bernard L. Silverman, M.D., and Reema L. Habiby, M.D. (Chicago, IL); Janet H. Silverstein, M.D. (Gainesville, FL); Dennis M. Styne, M.D. (Sacramento, CA); Larry C. Deeb, M.D. (Tallahassee, FL); Paul Saenger, M.D., and Joan R. DiMartino-Nardi, M.D. (Bronx, NY); David Finegold, M.D. (Pittsburgh, PA); Leona Cuttler, M.D. (Cleveland, OH); Robert McVie, M.D. (Shreveport, LA); Jerry S. Olshan, M.D. (Portland, ME); Robert A. Richman, M.D., and Susan Stred, M.D. (Syracuse, NY); Malcolm S. Schwartz, D.O. (Belleville, NJ); Paulo Solberg, M.D., and Nancy Friedman, M.D. (Durham, NC); and David H. Jelley, M.D. (Tulsa, OK).

Abbreviations: BMI, Body mass index; CI, confidence interval; T/E, testosterone/estradiol.

Received January 16, 2004.

Accepted May 27, 2004.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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