Gynaecomastia and breast cancer in men

Drugs, creams, cosmetics, and lotions

Body builders who use high doses of androgen frequently develop significant gynaecomastia, often with breast tenderness, because of androgen conversion to oestrogen.4 At the opposite end of the spectrum, men prescribed combined gonadotrophin releasing hormone agonist-androgen receptor antagonist therapy or androgen receptor antagonist monotherapy for prostate cancer develop gynaecomastia 10-20% and 50-60% of the time, respectively.5 Gynaecomastia is much less common in men taking 5 α reductase inhibitors for benign prostatic hypertrophy (0.3-1.1%).

Patients treated with highly active antiretroviral therapy for HIV report gynaecomastia, but the prevalence and mechanisms are uncertain.6 Pseudogynaecomastia can occur in patients with HIV associated lipodystrophy. HIV does not increase the risk for breast cancer, but HIV associated lymphoma can present as a lymphomatous breast mass.

Cosmetics, creams, and lotions may contain oestrogens or compounds with oestrogen effects. Children are particularly vulnerable to these sources. Three healthy prepubertal boys developed gynaecomastia, which was traced to repeated application of a “healing balm” containing lavender oil (Lavandula augustifolia), lavender scented soap and skin lotions, and shampoo and styling gel containing lavender and tea tree oil (Melaleuca alternifolia), respectively. Antiandrogenic effects of lavender and tea tree oil were confirmed using human breast cancer cell lines.7 Gynaecomastia resolved within a few months of stopping these applications.

Starvation and refeeding

Children and adults refed after starvation or who have been treated with growth hormone can develop transient gynaecomastia. The mechanisms are thought to be similar to those governing gynaecomastia during puberty.

Illness

Multiple mechanisms may operate in systemic diseases. Thyrotoxicosis increases production of androstenedione, increases oestrogen production in peripheral tissue, and increases sex hormone binding globulin levels. Androgen catabolism is reduced in liver disease, making more available for conversion to oestrogen in peripheral tissue. Renal failure has many effects on hormone and drug metabolism.

Tumours

All types of testicular tumours have increased aromatase activity.8 Leydig and Sertoli cell tumours produce androgen and oestrogen. Germ cell tumours produce intratesticular human chorionic gonadotrophin, which can cause dysfunction of Leydig cells and reduced testosterone production. Lung and hepatic tumours can produce enough systemic human chorionic gonadotrophin to increase Leydig cell testosterone secretion, which is readily converted to oestrogen through increased aromatase activity. Gynaecomastia may follow cancer treatment if chemotherapy or radiation damages Leydig cells.

Genetic causes

Several families (fathers and sons) have been described with oestrogen excess due to mutations activating the aromatase gene.9 They developed prepubertal gynaecomastia and accelerated prepubertal growth.

Examination

Table 3⇓ lists differences in the presentation of gynaecomastia and malignancy. If breast tissue enlargement is unilateral, a diagnosis other than gynaecomastia must be considered. In the absence of exogenous androgen or other drugs, rapid development of breast enlargement outside puberty suggests a tumour producing luteinising hormone or human chorionic gonadotrophin. Almost no lobular tissue exists in normal adult male breast tissue. Gynaecomastia is characterised by proliferation of ductules and loose connective tissue. Increasing glandular tissue in adult men increases the concern for malignancy.

Other important physical findings include adiposity, signs of hyperthyroidism, liver disease, hypogonadism (gynoid body habitus, decreased body hair, small testes consistent with Klinefelter’s syndrome), excessive musculature indicating exogenous androgen administration, or a testicular mass.

Initial laboratory evaluation

If the cause of breast enlargement is not obvious, laboratory evaluation is needed (fig 2⇓). Such evaluation is unnecessary for boys at puberty, for typical asymptomatic senile changes, for enlargement consisting mostly of adipose tissue, for men taking drugs known to cause gynaecomastia, or for physical findings strongly suggesting breast cancer.

Fig 2 Evaluation of non-physiological breast enlargement in men when cause is not obvious

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Imaging

Imaging is not necessary if cancer is not suspected. Ultrasonography and mammography can, however, differentiate adipose tissue from gynaecomastia and can be useful if surgical intervention is planned. Mammography is about 90% sensitive and 90% specific for malignant compared with benign masses in men.15 Invasive cancers are solid on ultrasonography. A complex cystic mass also is suspicious.

Biopsy

Biopsy is the only way to make a definitive diagnosis. Patients with a hard, irregular or asymmetrical mass, nipple discharge (bloody or non-bloody), axillary adenopathy, or a mass fixed to skin or the chest wall must have a biopsy (table 3⇑). Core biopsy is recommended over fine needle or excisional biopsy.

Most primary breast carcinomas in men are ductal, either invasive or non-invasive (ductal carcinoma in situ).16 Papillary histology is more common and lobular histology is rare in men (fig 3⇓). Ninety per cent of breast cancers in men have oestrogen and progesterone receptors.

Fig 3 Histology of breast cancers in men and women

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Non-surgical treatment

Physiological gynaecomastia requires no treatment unless accompanied by pain or significant embarrassment. Withdrawing an offending drug or treating an underlying disorder may be sufficient, especially if gynaecomastia is relatively recent.

Testosterone replacement for hypogonadal men can be beneficial, but longstanding fibrotic gynaecomastia is unlikely to respond. One small study showed more stable testosterone levels and more resolution of gynaecomastia with transdermal testosterone than with biweekly intramuscular testosterone injections that resulted in high initial testosterone levels with potential to cause high oestrogen levels.17 Danazol, a weak androgen, is less effective.

Anti-oestrogen treatment with tamoxifen 10-20 mg/day significantly reduced pain and breast volume in 40-80% of boys with persistent pubertal gynaecomastia18 and men with prostate cancer treated with an androgen receptor blocker (bicalutamide).19 Trials of raloxifene and clomiphene are too small or results too mixed to be conclusive. The aromatase inhibitor anastrazole was no better than placebo for reducing breast volume during puberty20 and was less effective than tamoxifen in men treated with bicalutamide.19

Local irradiation (10-12 Gy) prevented gynaecomastia in men with prostate cancer treated with bicalutamide,20 but tamoxifen achieved significantly better results.21

Surgical treatment

Men with findings suspicious for malignancy or gynaecomastia causing persistent pain or embarrassment should be referred to a surgeon. Goals of surgery include removing abnormal breast tissue, restoring the normal male breast contour, and reducing pain.

Liposuction is effective if breast enlargement is mostly caused by adipose tissue and the overlying skin is fairly taut. Subcutaneous mastectomy is required for removal of glandular tissue and redundant skin (visible inframammary skinfolds) and pain relief. Complications include haematoma, seroma, infection, sensory changes, pain, breast asymmetry, skin redundancy, and scarring.22 23 The most common complication is a poor cosmetic outcome. Final results of surgery may not be apparent for a year.