• 
• 

Three Part Question

In [boys with pubertal gynaecomastia] is [anastrozole or tamoxifen] [effective in reducing breast tissue and which is more effective]?

Clinical Scenario

Tom is a 12-year-old boy who presents with a 6-month history of breast enlargement. He is extremely embarrassed about the size of his breasts and avoids sport because he does not want to be seen while getting changed. He wonders if anything can be done to reduce the size of his breasts.

Tom has Tanner stage III breast development. He has entered puberty and his height and weight are both on the 99th centile. He has a male karyotype and his hormone levels are all within the normal range.

As Tom is so distressed, you decide that something needs to be done. You have heard that anti-oestrogens, such as tamoxifen, and aromatase inhibitors, such as anastrozole, can be used to treat pubertal gynaecomastia. You start Tom on 10 mg of tamoxifen daily, but after 6 months of treatment this has made little difference to the size of his breasts. You wonder whether anastrozole would be a more effective therapy.

Search Strategy

The primary source was PubMed, using the search terms “(tamoxifen OR anastrozole) AND pubertal AND gynaecomastia”.


A secondary search using the Cochrane Database, Best Evidence and Clinical Evidence did not find any additional relevant articles.

Search Outcome

Fourteen items were found (last checked in July 2009), of which six were selected as relevant. Only one randomised controlled trial was found. There have not been any studies to compare the efficacy of the two drugs.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Lawrence et al, 2004	38 Boys with persistent pubertal gynaecomastia	Retrospective cohort study (level 2b)	Decrease in breast size in response to tamoxifen, raloxifene or no treatment	Raloxifene: mean reduction in breast size: 2.5 cm (66%) (95% CI 1.7 to 3.3, p<0.0001). Decrease in gynaecomastia in 86% of breasts Tamoxifen: mean reduction in breast size: 2.1 cm (46%) (95% CI 1.7 to 2.7, p<0.0001). Decrease in gynaecomastia in 91% of breasts No treatment: 50% self-reported spontaneous resolution of gynaecomastia	The control (no treatment) group was not formally followed up. It is not clear whether treatment was more effective than observation alone.
			“Positive response to treatment” (>50% reduction in breast size)	Raloxifene: 86% Tamoxifen: 41% All but one of the patients in the treatment groups showed a decrease in gynaecomastia by 6–9 months
			Recurrence	No recurrence in either group
			Side effects	No side effects
			Satisfaction	40% of patients in each group went on to have surgery
Derman et al, 2003	37 Boys with pubertal gynaecomastia	Case series (prospective study) (level 4)	Efficacy of tamoxifen (10 mg twice daily) in reducing breast size	Size reduction in all patients (dose increased to 20 mg twice daily in three patients owing to poor response initially)	No control group: breast tissue may have regressed spontaneously. No long-term follow-up reported.
			Pain reduction	Pain reduction in all patients
			Recurrence	Recurrence in 2 patients
			Satisfaction	No patients referred for surgery
			Side effects	No long-term side effects
Derman et al, 2008	10 Boys with pubertal gynaecomastia	Case series (prospective study) (level 4)	Efficacy of tamoxifen (10 mg twice daily) in reducing breast size	Breast nodule palpable in only one patient after 2.5–7 years Dose increased to 20 mg twice daily in one patient owing to poor response after 4 months of treatment Complete remission of all signs and symptoms of gynaecomastia	No control group: breast tissue may have regressed spontaneously
			Recurrence	None
			Side effects	No hot flashes, nausea, vomiting, skin rashes or vertigo
			Long-term effects	Osteopaenia in one patient Sex-hormone binding globulin levels decreased in seven patients No negative effects on growth, Tanner stage, testicular volume, body mass index, bone age or any hormonal parameter
König et al , 1987	10 Boys with pubertal gynaecomastia	Case series (prospective study) (level 4)	Efficacy of tamoxifen 20–40 mg/day in reducing breast size	Gynaecomastia totally regressed in 8/10 boys after 2–12 months of treatment	Small sample size. No control group. No long-term follow-up It seems odd that breast size decreased despite an increase in oestradiol levels. The authors suggest that the mean therapeutic effect of tamoxifen is through blockade of the oestrogen receptors of the breast tissue
			Side effects	None noted
			Hormone levels	Levels of oestradiol and testosterone increased during treatment. There was a more pronounced increase in oestradiol
Plourde et al, 2004	80 Boys with pubertal gynaecomastia	Randomised, double-blind, placebo-controlled trial (level 1b)	Efficacy of anastrozole 1 mg daily (or placebo) in reducing breast volume (positive response: >50% reduction in breast volume)	Anastrozole group: positive response in 38.5% of patients Placebo group: positive response in 31.4% of patients. Odds ratio 1.513; 95% CI 0.496 to 4.844; p=0.47 (no signifi cant difference between the two groups). Complete regression of breast tissue in one patient in anastrozole group	This study used ultrasonography measurements of breast volume (rather than breast size) to measure response to treatment. This may well be a more accurate measurement of breast tissue. Reasonable sample size but may not have been large enough to observe a significant difference between active drug and placebo treatment groups. Patients in this study had all had gynaecomastia for 6 months. 91% had a disease duration of greater than 1 year. A greater response to treatment may have been seen within the first 6 months of gynaecomastia (during active proliferation of breast tissue). Long-term safety and efficacy of anastrozole was not studied.
			Hormone levels	Change in the testosterone/oestradiol ratio at 6 months: 166% for the anastrozole group; 39% for the placebo group.
			Side effects	Minor side effects reported. No serious adverse events. Anastrozole was discontinued in one patient because of testicular enlargement
			Pain reduction	Breast pain resolved in 10/11 patients in anastrozole group and all patients in placebo group
Riepe et al , 2004	5 Boys with pubertal gynaecomastia and breast tenderness	Case series (prospective study) (level 4)	Efficacy of anastrozole (1 mg daily for 6 months) in reducing breast size	Breast size decreased in four out of fi ve patients. Complete regression in one of the four boys	Boys in this study had had gynaecomastia for 10.2±4.8 months prior to treatment. The patient with the poorest response to treatment had had gynaecomastia for the longest period (18 months). Very small sample size
			Breast tenderness	Breast tenderness resolved in all boys within 4 weeks
			Side effects	None noted
			Hormone levels	Testosterone/oestradiol ratio increased signifi cantly during the treatment

Comment(s)

Pubertal gynaecomastia is breast enlargement without any pathological cause in adolescent boys. It is thought to arise from a transient imbalance between the stimulatory effects of oestrogens and the inhibitory effects of androgens on breast tissue during puberty. It is a common problem, affecting 48–64% of boys at puberty to some degree. In more than 90% of cases it resolves spontaneously within 3 years (Khan). However, gynaecomastia occurs at a time when boys are most aware of their self-image and the condition may be psychologically disabling.

There are currently three options for managing pubertal gynaecomastia: Reassurance is widely regarded as the safest and most reasonable form of “treatment”, as the condition is usually asymptomatic and self-limiting. Surgery may be considered in boys who are not obese when there is significant breast tenderness or psychosocial morbidity. However, surgery is associated with complications such as scarring, skin retraction and hypesthesia (Sltzstein). Also, the condition may recur postoperatively.

Tamoxifen is a selective oestrogen receptor modulator which has anti-oestrogenic effects on breast tissue. Lawrence et al reported a decrease in breast size in 20 out of 22 breasts (91%) after treatment with tamoxifen, with a greater than 50% reduction in 41%, but 40% of patients were not entirely satisfied and went on to have surgery (Lawrence). Two case reports showed a decrease in breast size and other associated symptoms in virtually all cases and no recurrence following treatment (Derman, König ).

Derman et al assessed the long-term effects of tamoxifen, showing after 2.5–7 years that there was complete remission of all signs and symptoms. Only one boy had a palpable breast nodule. Despite these positive results, the studies are difficult to interpret because of the small sample populations and the absence of placebo-treated controls. Even in the cohort study, the boys who received reassurance alone (ie, no treatment) were not formally followed up.1 As many patients experience spontaneous regression of breast tissue, it is unclear whether these positive results are due to the pharmacological effects of the drug or some subtle case mix or selection bias.

Only two studies have investigated the effectiveness of anastrozole in the treatment of pubertal gynaecomastia. One well-designed randomised controlled trial found that anastrozole was not significantly more effective than placebo in reducing breast size and tenderness (Plourde). Only one patient had an adverse reaction to anastrozole. These results were largely supported by a small case study (Riepe).The long-term effects of treatment with anastrozole are unknown. Whereas tamoxifen is a selective oestrogen receptor modulator which has an antagonistic effect only on breast tissue, anastrozole reduces the effect of oestrogen in all tissues, including bone and lipids. Concerns have been raised over potential long-term adverse effects of anastrozole on growth, bone maturation and lipid profile. There have been no studies evaluating the efficacy of tamoxifen and anastrozole in the treatment of pubertal gynaecomastia. Comparing these observational studies, the response rate (>50% reduction in gynaecomastia) to tamoxifen (41%) Lawrence, was marginally higher than that to anastrozole (38.5%),Plourde. yet this was not significantly better than placebo (31.4%). This is in keeping with a randomised controlled trial that compared tamoxifen with anastrozole and placebo in preventing gynaecomastia induced by bicalutamide in men with prostate cancer (Saltzstein).

Further studies, in the form of randomised, placebo-controlled trials, using breast ultrasonography as a more accurate measurement of glandular tissue, are needed in order to more reliably assess the natural progression of the disease and the efficacy of pharmacological treatment. Many questions remain unanswered, including the optimum dose, duration and timing of treatment. As gynaecomastia is a cosmetic condition, it would be valuable to assess the psychosocial impact of pharmacological treatment. Pharmacological treatment aims to correct the imbalance of oestrogens and androgens that is thought to cause proliferation of breast tissue. Several drugs are reported in the literature. Tamoxifen, raloxifene and clomiphene block the effects of oestrogen on the breast, while anastrozole and testolactone inhibit its production. Danazol (an androgen) acts to counterbalance the stimulatory effects of oestrogens.

Clinical Bottom Line

Tamoxifen appears to be safe and possibly effective in reducing the size of glandular tissue in persistent pubertal gynaecomastia, but may be ineffective in reducing breast tissue completely and eliminating the need for future surgery. (Grade B) Anastrozole may not be more effective than placebo in decreasing the size or volume of breast tissue in persistent pubertal gynaecomastia and its long-term effects and safety are still unknown. (Grade D) Pharmacological management of gynaecomastia has not been formally assessed from a psychological perspective. (Grade D)

References

1. Lawrence SE, Faught KA, Vethamuthu J, et al. Beneficial effects of raloxifene and tamoxifen in the treatment of pubertal gynecomastia. J Pediatr 2004;145:71–6.
2. Derman O, Kanbur NO, Kutluk T. Tamoxifen treatment for pubertal gynecomastia. Int J Adolesc Med Health 2003;15:359–63.
3. Derman O, Kanbur N, Kilic I, et al. Long-term follow-up of tamoxifen treatment in adolescents with gynecomastia. J Pediatr Endocrinol Metab 2008;21:449–54.
4. König R, Schönberger W, Neumann P, et al. [Treatment of marked gynecomastia in puberty with tamoxifen]. Klin Padiatr 1987;199:389–91.
5. Plourde PV, Reiter EO, Jou HC, et al. Safety and efficacy of anastrozole for the treatment of pubertal gynecomastia: a randomized, double-blind, placebo-controlled trial. J Clin Endocrinol Metab 2004;89:4428–33.
6. Riepe FG, Baus I, Wiest S, et al. Treatment of pubertal gynecomastia with the specific aromatase inhibitor anastrozole. Horm Res 2004;62:113–18.
7. Khan HN, Blamey RW. Endocrine treatment of physiological gynaecomastia. BMJ 2003;327:301–2.
8. Colombo-Benkmann M, Buse B, Stern J, et al. Indications for and results of surgical therapy for male gynecomastia. Am J Surg 1999;178:60–3.
9. Saltzstein D, Cantwell A, Seiber P, et al. Prophylactic tamoxifen significantly reduces the incidence of bicalutamide-induced gynaecomastia and breast pain. Br J Urol Int 2009;90(Suppl 2):120–1.