Tamoxifen Treatment for Pubertal Gynecomastia: When to Start and How Long to Continue

Abstract

Introduction

Pubertal gynecomastia is a common clinical condition among male adolescents, and in most cases, it regresses spontaneously. However, tamoxifen treatment is recommended in selected cases. We aimed to evaluate the indications, safety, and efficacy of tamoxifen treatment in adolescents with pubertal gynecomastia.

Methods

The data of 83 adolescents with pubertal gynecomastia who were treated with tamoxifen between 2006 and 2018 were evaluated retrospectively. The clinical and laboratory data, initial complaint, tamoxifen treatment indication, duration, and dose were recorded along with the treatment outcome.

Results

The gynecomastia disc diameter’s monthly reduction rate was significantly higher in adolescents with an initial disc diameter ≥3 cm. The significant reduction of the disc started after the fourth month of tamoxifen treatment and continued to significantly reduce, extending to the sixth month.

Conclusion

Tamoxifen treatment in pubertal gynecomastia was found to be effective and safe. One of the current indications for tamoxifen treatment is having a disc size ≥4 cm, and the recommended treatment duration is 4–6 months. However, this study suggests that treatment should be continued for at least 6 months to achieve the optimal effect. In addition, we recommend that the disc diameter threshold for starting tamoxifen needs to be ≥3 cm.

Introduction

The prevalence of pubertal gynecomastia (PG) varies between 3.9 and 64.6%, depending on diagnostic criteria used [1]. Its etiology is likely multifactorial, involving a decrease in the androgen-to-estrogen ratio, increased aromatase enzyme activity, and/or sensitivity. PG usually occurs 6 months after the onset of male secondary sex characteristics and tends to resolve within 1–2 years [2, 3]. However, PG persists in less than 10% of cases [4]. To date, there are no universal guidelines for PG treatment, but common clinical practices include selective estrogen receptor modulators (SERMs), aromatase inhibitors, and androgen-like agents [2].

As Hacettepe University Children’s Hospital Adolescent Medicine Clinic, we recommend pharmacological therapy for breast disc diameters of 4–6 cm, disc diameters less than 4 cm with symptoms persisting for at least 1 year, and/or PG causing significant pain, embarrassment, emotional stress, and affecting social and physical functioning [5]. Our standard treatment protocol is tamoxifen, a SERM, used at a dose of 10 mg orally twice a day for 6 months [6]. During treatment, adolescents are screened monthly for the rare side effects of elevated liver enzymes, leukopenia, and thrombocytopenia. When the disc disappears or decreases below 5 mm after 6 months of treatment, tamoxifen is discontinued. This study aimed to retrospectively evaluate the complaints, clinical and laboratory findings, treatment outcome, and side effects of tamoxifen in adolescents with PG who were treated with tamoxifen in the last 12 years to provide scientific data for future studies and treatment guidelines.

Methods

Study Population

A total of 83 male adolescents who received tamoxifen treatment for PG in the Adolescent Medicine Clinic of Hacettepe University Children’s Hospital between January 2006 and January 2018 were included in this study. The electronic medical records of the adolescents with PG were retrospectively evaluated for clinical and laboratory findings. Since PG is not included in the International Statistical Classification of Diseases and Related Health Problems (ICD 10) diagnostic codes, the following three codes we believed corresponded to PG were used: “hypertrophy of the breast,” “undefined mass in the breast,” and “other defined disorders of the breast” were screened on the electronic medical records system of the hospital. The medical records (electronic records and patient files) of these patients were assessed, and a final number of 83 male adolescents who received tamoxifen treatment for PG were included in the study. The flowchart of inclusion is presented in Figure 1.

Fig. 1.

Inclusion flowchart.

Measurements

Body weight, height, body mass index (BMI), and ideal body weight percentage of each patient at the time of admission and at monthly clinical visits were noted. Center for Disease Control and Prevention (CDC) percentiles were used to evaluate the anthropometric measurements. BMI was calculated as the ratio of weight (kg) to the square of height in meters (m) (BMI = weight [kg]/height² [m²]) [7]. According to BMI percentiles, patients were categorized into 4 groups: ≤15 p as underweight, 15–85 p as normal weight, 85–95 p as overweight, and ≥95 p as obese. Tanner’s pubic hair stage and testicular volumes during the initial admission were recorded. The longitudinal sizes of left and right PG discs were evaluated separately.

A complete blood count (leukocyte and thrombocyte count), transaminases (alanine aminotransferase and aspartate aminotransferase), follicle-stimulating hormone, luteinizing hormone, total testosterone, estradiol, sex hormone-binding globulin, prolactin, human chorionic gonadotropin, dehydroepiandrosterone sulfate, thyroid function tests, and the bone age results were assessed to exclude pathological causes. The indications, duration, and the doses of the tamoxifen treatment were noted. Any comorbidities or any other medications were also noted. The monthly follow-up results of the complete blood count and transaminase levels were recorded along with any other side effects of tamoxifen.

The treatment response was assessed by analyzing the PG disc size during the monthly follow-up visits. A disc diameter of ≤0.5 cm at the end of the treatment was classified as “complete remission,” a reduction of ≥0.5 cm in the pretreatment disc diameter was grouped as “decreased disc diameter,” and a stable or increased disc diameter after treatment was classified as “unresponsive disc diameter.” A positive treatment response was defined as having a “decreased disc diameter” or a “complete remission.”

The difference between the initial disc diameter and the disc diameter measured in any given month was defined as the delta (Δ) disc diameter for that month. The relationship between the initial and the monthly Δ disc diameters was evaluated separately for the right and left discs. During this evaluation, comparisons were made using two different thresholds for the initial disc sizes: ≥3 cm and ≥4 cm.

Statistical Analysis

Study data were analyzed using SPSS 23.0. Mean ± standard deviation for normally distributed data and the median largest and smallest values for those who did not show calculated normal distribution. The relationship between qualitative variables was examined using the χ² test. When comparing the groups, the significance test of the difference between the two means (t test in independent groups) was used for the data showing normal distribution. The Mann-Whitney U test was used for the data that were not normally distributed. To examine the relationship between two numerical variables, the Pearson correlation coefficient was used for normally distributed data. The Spearman correlation coefficient was used for the data that did not show normal distribution. A p < 0.05 was accepted as a statistical significance for all data.

Results

The mean age of the patients was 14.12 ± 1.43 years at the initial admission; 29 (36.7%) patients were in Tanner stage 4, and 18 (22.8%) were in Tanner stage 5. The clinical and laboratory data from the initial admission, including anthropometric measurements, right and left PG disc diameter, testicular volume, complete blood count, alanine aminotransferase and aspartate aminotransferase values, hormone levels, and bone age, are given in Table 1. No significant association was found between the hormonal levels and the initial disc diameters (p > 0.05).

Table 1.

Clinical and laboratory data of adolescents with PG at the initial admission

	Number	Mean±standard deviation (min–max value)
Calendar age, year	83	14.12±1.43 (11.16–17.58)
Bone age, year	26	14.3±1.51 (12–17)
Body weight, kg	81	64±13.58 (32–113.5)
Length, cm	81	165.97±8.80 (144–190)
BMI, kg/cm2	81	23.09±3.89 (14.91–34.17)
BMI percentile, %	81	0.74±0.25 (0.01–1)
BMI Z score	81	0.96±0.93 (−2.61–3.48)
Right disc diameter, cm	79	3.13±1.25 (0–6)
Left disc diameter, cm	79	3.13±1.13 (0–5)
Leukocyte count, ×10³/µL	77	6.80±1.57 (3.9–11.5)
Platelet count, ×10³/µL	77	285.6*10³±66.3*10³ (149*10³–479*10³)
ALT, U/L	78	18.99±9.04 (8–53)
AST, U/L	77	23.86±5.53 (15–46)
FSH, mlU/mL	82	3.22±2.04 (0.77–13.69)
LH, mlU/mL	81	2.08±1.34 (0–6.81)
Estradiol, pg/mL	55	21.52±11 (0–59.19)
Total testosterone, ng/dll	78	247.60±187 (3.25–892.99)
DHEASO4, µg/mL	66	186±97.94 (27.50–489)
Prolactin, ng/mL	70	9.94±4.44 (3.02–24.80)
TSH, ulU/mL	78	4.00±10.90 (0.81–98.40)
SHBG, nmol/L	60	29.62±18.92 (10–126)
β-HCG, mlU/mL	67	1.22±0.43 (0.09–2)

ALT, alanine aminotransferase; AST, aspartate aminotransferase; FSH, follicle-stimulating hormone; LH, luteinizing hormone; DHEAS, dehydroepiandrosterone sulfate; TSH, thyroid-stimulating hormone; SHBG, sex hormone-binding globulin; β-HCG, human chorionic gonadotropin.

The indications for starting the tamoxifen treatment are given in Figure 2. Of the 83 patients, the most common reason was having gynecomastia for more than a year (44%). Clinical and laboratory data during the 6-month follow-up of patients using tamoxifen are given in Table 2. There was no statistically significant change in the monthly anthropometric measurements, transaminase, leukocyte, and platelet counts. A patient’s drug dose was doubled after the fourth month of treatment, but the treatment was discontinued due to a minimal increase in liver enzymes. No other side effects were recorded.

Fig. 2.

Indications for tamoxifen treatment.

Table 2.

Testicular volume and initial and posttreatment disc diameter measurements according to the Tanner stages

Tanner stage	Number (%)	Testicular volume, cm³	Initial right disc diameter, cm	Initial left disc diameter, cm	Posttreatment right disc diameter, cm	Posttreatment left disc diameter, cm
2	5 (6.4)	8±2 (6–10)	3.5±0.7 (3–4.5)	3.6±0.9 (3–5)	1.4±1.1 (0–2.5)	1.7±1.4 (0–3)a, b
3	27 (34.6)	12.4±4.41 (6–20)	3.4±1.1 (0.5–6)	3.3±1 (1–5)	1.5±1.4 (0–4)	1.2±1.4 (0–5)a, b
4	29 (37.2)	17.44±4.27 (12–25)	3.1±1.4 (0–5)	3.4±0.8 (2–5)	1.5±1.4 (0–4.5)	1.8±1.3 (0–5)a
5	17 (21.8)	22.5±3.16 (15–25)	2.8±1.4 (0–5)	2.4±1.6 (0–5)	0.5±0.8 (0–2)	0.6±0.9 (0–2.5)b

The pubertal staging data of five adolescents could not be found in the medical records.

For posttreatment left disc diameter, the stages with different letters (a, b) are significantly different. The values are presented as mean ± standart deviation (minimum-maximum).

According to Tanner stages, the initial right and the left disc diameters were not statistically different (p = 0.150) (Table 2). While the posttreatment right disc diameters were not different according to Tanner staging, the posttreatment left disc diameters were statistically different between Tanner stages 4 and 5 (p = 0.006) (Table 2).

The mean duration of tamoxifen treatment was 4.1 ± 2.01 (1–8) months. In 74 (93.67%) of the adolescents, the PG were either in complete remission or the disc size had significantly decreased by the end of the treatment (Table 3). The chronological age was significantly greater in the “complete remission” group compared to the “decreased diameter” group (t = 2.11, p = 0.041).

Table 3.

Chronological age, bone age, initial and posttreatment disc diameters, and treatment durations according to treatment response

Disc condition	Number (%)	Chronological age, years	Bone age, years	Initial right disc diameter, cm	Initial left disc diameter, cm	Posttreatment right disc diameter, cm	Posttreatment left disc diameter, cm	Treatment duration, months
Complete remission	27 (34.2)	14.6±0.7 (12–17.6)	13.9±1.45 (12–17)	3±1.3 (0–5)	2.9±1 (0–4.5)	0.2±0.6 (0–2)	0.3±0.6 (0–3)	4.8±1.9 (1–8)
Diameter decreased	47 (59.5)	13.8±1.61 (12–16.9)	14.5±1.61 (12–17)	3.3±1.2 (0–6)	3.3±0.9 (1–5)	1.5±1.1 (0–4)	1.6±0.7 (0–5)	4.2±1.9 (1–8)
Diameter increased	5 (6.3)	14.5±1.7 (12–16.3)	15.5±0.7 (15–16)	2.8±1.3 (1–4.5)	3.2±0.6 (2–4.5)	3.8±0.6 (3–4.5)	3.4±1.2 (2–5)	2.8±1.8 (1–5)

The values are presented as mean ± standart deviation (minimum-maximum).

For the right disc, there was a statistically significant difference between the initial measurement and the measurements in the fourth, fifth, and sixth months of treatment (p = 0.007, p = 0.004, p = 0.000, respectively), but no significant difference was found during the first 3 months. Similarly, for the left disc, there was a statistically significant difference between the initial measurement and the measurements in the fifth and sixth months of treatment (p = 0.045, p = 0.006, respectively). No significant difference was found for the first 4 months.

The Δ disc diameters for any given month (1–6 months) were significantly higher in PG discs with an initial diameter of ≥3 cm than <3 cm (t = −4.9, p = 0.000 for the right breast; t = −2.13, p = 0.37 for the left breast). In PG discs ≥3 cm, the mean Δ disc diameter in the first month was significantly lower than the fourth and fifth months (p = 0.021, p = 0.011, respectively) (Fig. 3). No significant difference was observed in the PG discs <3 cm group’s Δ disc diameters of any other months (p = 0.870).

Fig. 3.

a Monthly Δ disc diameters in adolescents with initial breast disc diameters of ≤3 cm. b Monthly Δ disc diameters in adolescents with initial breast disc diameters of ≥3 cm.

However, when the initial disc diameter cutoff was taken as 4 cm, we found that the mean Δ disc diameters of the first, second, and fourth months were significantly higher in ≥4 cm group compared to <4 cm (t = −3.87, p = 0.000 for the right breast and t = −2.33, p = 0.22 for the left breast). No significant difference was found between the Δ disc diameters of any given month neither in the ≥4 cm nor in the <4 cm groups (p = 0.610).

Thirty-eight (46.9%) patients were overweight or obese. Disc diameters were significantly higher at the time of admission and at the first and second months of treatment in the overweight/obese adolescents compared to the normal-weight group (p = 0.016 for right disc diameter, p = 0.025 for left disc diameters). In the third month of treatment, no difference was observed (p = 0.990, p = 0.680). Monthly Δ disc diameters were not significantly different between overweight/obese and normal-weight patients (z = −1.82, p = 0.760).

Discussion

Our study analyzed 83 male adolescents with PG who were treated with tamoxifen out of a total of 442 cases between 2006 and 2018. According to our retrospective analysis, we arrived at two important conclusions regarding tamoxifen treatment for PG. Our study recommends a lower disc diameter cutoff of 3 cm to start tamoxifen. Additionally, we suggest tamoxifen treatment cessation after six months of treatment.

In our study, adolescents with an initial disc diameter of ≥3 cm showed a more significant reduction rate in disc diameter per month with tamoxifen treatment compared to the 4 cm cutoff. Considering the level of treatment efficacy, we suggest starting tamoxifen at a disc size of 3 cm instead of the current empirically determined cutoff of 4 cm.

The cumulative cases over years and higher sample size in this study have also enabled detailed statistical analyses that could not be conducted in our previous studies [5]. Previous studies recommended 4–6 months of tamoxifen treatment for PG [2, 5, 8] based on empirical data, clinical observations, and experiences. However, no scientific evidence was available for the optimal treatment duration. In this study, the significant reduction in disc diameter starting from the fourth month and continuing till the sixth month indicates that a “6-month” duration is optimal for achieving maximal efficacy.

We suggest promptly administering medical treatment in cases where PG has existed for more than a year, even if the size is less than 4 cm, due to the risk of fibrosis [9]. When significant pain is concomitant with PG, tamoxifen treatment may be considered regardless of disc size. We found that the most common tamoxifen indication (43%) was persistent PG followed by significant breast pain (29%) and negative psychosocial outcomes (15%). During adolescence, having and maintaining a body perception that is physically and sexually pleasing is important for positive identity development. The association between PG and internalization disorders, negative body perception, and self-esteem has been demonstrated in various studies [10–12]. A previous study in our clinic showed that tamoxifen treatment led to positive improvements in body perception beginning from the first month of treatment [13].

Tamoxifen treatment response rate in our clinic was found to be above 80% in previous studies [14–16]. This current study is the largest case series from our clinic, and the treatment success was calculated at 94%, the highest among our reports. However, these results should be evaluated carefully considering the lack of a control group in which tamoxifen was not started despite the treatment indication. In a 10-year prospective cohort study conducted primarily in the adult age group (n = 81, mean age: 42.8 ± 19.5 years), the response rate was calculated as 90.1%, highlighting that tamoxifen is an efficient treatment choice in idiopathic gynecomastia [17]. A systemic review of pharmacological treatments of PG reported that tamoxifen produced significant changes in 74–95% of the patients [18]. Both of these studies have focused on the treatment outcomes and not particularly on the indications of treatment.

In our study, posttreatment left disc diameters were higher in Tanner stage 4 compared to 5, suggesting that treatment response depends on pubertal stage. Also, adolescents with complete disc disappearance were significantly older than those with reduced disc diameters. In parallel with the pubertal growth, the growth rate and prevalence of PG peak in Tanner stages 3 and 4 and decline in stage 5 [1, 19]. Therefore, as the expected growth rate of PG disc is higher during the early stages of puberty and slows down toward the end of puberty, the effectiveness of tamoxifen becomes more visible, and complete disappearance of the disc is more frequent in stage 5 [14, 15].

In this study, 46% of the patients who were started on tamoxifen were overweight or obese, which is higher than the general population [20]. It has been shown that aromatase enzyme expression in adipose tissue is higher in patients with PG [21]. In this study, overweight/obese adolescents had higher disc diameters before and during the first 2 months of the treatment as well. As of the third month of treatment, no difference was observed between the overweight/obese and normal-weight adolescents in terms of disc sizes. This suggests that tamoxifen, a SERM, is an effective choice of medication in this particular patient group with higher aromatase enzyme activities due to increased adipose tissue.

The strength of this study is that the number of our cases is high enough to allow detailed statistical analyses that could not be done in any of our previous studies. This study provides scientific evidence regarding the disc size-efficacy relationship and treatment duration. The limitations are the lack of longitudinal follow-up data longer than 6 months and missing follow-up data of a few patients who did not attend some of their appointments in our clinic. Furthermore, the absence of a control group is another limitation, but it was not possible to establish a suitable control group due to the retrospective nature of the study. In addition, it is considered ethically inappropriate not to start tamoxifen when the treatment is indicated.

Conclusion

Tamoxifen is safe and effective for treating PG in adolescents. Currently, the suggested duration of tamoxifen treatment for PG is 4–6 months, and this duration is determined based on clinical observations. The findings of this study showed that tamoxifen should be continued for 6 months to achieve the optimal effect. Furthermore, this study suggests starting tamoxifen treatment for PG discs with a diameter of ≥3 cm instead of the currently recommended ≥4 cm. These results provide scientific evidence for guiding future prospective studies and informing treatment guidelines.

Statements of Ethics

The Ethical Review Board of Hacettepe University Non-Interventional Clinical Research approved this study in December 2018 (approval number: GO 18/1119-21). The research was conducted ethically in accordance with the World Medical Association Declaration of Helsinki. Written informed consent from participants was not required in accordance with local/national guidelines.

Conflict of Interest Statement

The authors have no conflicts of interest to disclose.

Founding Sources

The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

Author Contributions

Design: Elif Sabancı and Nuray Kanbur; data collection: Elif Sabancı; data analysis: Elif Sabancı and Melis Pehlivantürk-Kızılkan; drafting of the manuscript: Elif Sabancı, Melis Pehlivantürk-Kızılkan, and Nuray Kanbur; and critical revision: Melis Pehlivantürk-Kızılkan, Sinem Akgül, Orhan Derman, and Nuray Kanbur.

Funding Statement

The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

Data Availability Statement

All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.