9.4.17 Gynaecomastia

Parenchymal and stromal cells with the potential for normal breast development are equally present in prepubertal boys and girls. Men and women do not differ in sensitivity to the hormonal action of sex steroids, and therefore men have the same potential to develop breasts as women. Whether this actually occurs obviously depends on a person’s hormonal milieu. In order to understand the pathophysiology of gynaecomastia it is essential to know that breast tissue is, for its development, under control of both stimulatory hormonal action (oestrogens and progestogens) and inhibitory hormonal action of androgens. Gynaecomastia typically occurs when there is a relative dominance of oestrogenic over androgenic action; many cases of gynaecomastia are not the result of an overproduction of oestrogens per se, but rather due to the failing inhibitory action of androgens (1). In the assessment of gynaecomastia, as much attention must be paid to a potential source of feminizing hormones as to decreased androgen production or interference with the biological action of androgens.

Oestrogens stimulate the proliferation and differentiation of parenchymal ductal elements while progesterone supports alveolar development. The biological actions of oestrogens and progesterone do not appear in cases of growth hormone deficiency. Prolactin stimulates the differentiated ducts to produce milk. Testosterone inhibits the growth and differentiation of breast development, probably through an antioestrogenic action (1).

Whatever the cause, gynaecomastia shows the same histological developmental pattern. At first, there is florid ductal proliferation, with epithelial hyperplasia and increase in stromal and periductal connective tissue, with increased vascularity and periductal oedema. After approximately one year, there is increased stromal hyalinization, dilation of the ducts, and a marked reduction in epithelial proliferation, a ‘burnt-out’ phase of the condition. The result is inactive fibrotic tissue which no longer responds to endocrine therapy.

Gynaecomastia is not an uncommon finding and most cases will not represent a serious medical condition. However, gynaecomastia may signify the presence of a malignancy producing oestrogens, aromatase (the enzyme that converts androgens to oestrogens), or human chorionic gonadotrophin (hCG). Common locations of such tumours are the testis, lungs, liver or the gastrointestinal tract. Consequently, cases of gynaecomastia must be taken seriously and the diagnostic approach must reasonably rule out a malignancy in order to avoid any undue delay in its diagnosis.

Gynaecomastia may occur when there is an imbalance between the feminizing effects of oestrogens (or oestrogenizing compounds) and the inhibitory action of androgens on mammary glandular tissue (Box 9.4.17.1). There may be an outright overproduction of oestrogens, but more often it is the failing androgenic inhibition of mammary tissue that is involved. The latter may be due to deficient testicular androgen production, but may also be caused by impaired biological availability or expression of androgen effects at tissue level. Testosterone is largely bound to carrier proteins. Sex hormone-binding globulin (SHBG) binds approximately 60% of testosterone in the circulation. Conditions such as chronic liver disease and hyperthyroidism are associated with an elevation of SHBG and thereby limit the bioavailability of testosterone. Androgen receptor defects may impair androgen action. Drugs and other chemical substances may have oestrogenic capacity or, alternatively, may interfere with androgen action. In the laboratory work-up of a patient, more often than not, no clear-cut endocrine abnormality can be found, sometimes explained by the fact that hormone levels in peripheral blood do not necessarily reflect hormone activity at tissue level (1, 2).

At some stages of life gynaecomastia may be physiological, provided it is transient and/or moderate. Newborns may have a degree of gynaecomastia, occasionally with galactorrhoea, due to the exposure to maternal/placental oestrogens. It regresses spontaneously over several weeks (3). In (early) puberty a significant number, as many as 30–65%, of boys at the age of 14 years will show a degree of gynaecomastia; usually the diameter of the glandular tissue will not exceed 1 cm, and it usually regresses (2). If gynaecomastia persists, in most instances the glandular tissue has become fibrotic. Pubertal gynaecomastia probably results from the relative excess of oestrogens in the early stages of testicular steroidogenesis, before adult rates of testosterone are produced (2). Gynaecomastia is not rare in men aged over 65 years; its mechanism is not fully clear (4). Plasma oestrogens may increase with age, but the explanation is probably rather the decline of androgens in ageing men, particularly in men with chronic disease (5).

Oestrogens may be produced by testicular Leydig and Sertoli cell tumours. Androgens are precursors for the formation of oestrogens by aromatase, which is present in the testis and also in peripheral tissues, including the breast. Testicular tumours producing aromatase and genetic defects with increased activity of aromatase are rare. Increased availability of androgen precursor for aromatization to oestrogens, as occurring in adrenal tumours and enzymatic blocks of adrenal hormones, may increase oestrogen levels. Chronic liver disease and hyperthyroidism are also associated with increased oestrogen synthesis, but SHBG levels are also increased, leading to a lower bioavailability of androgens and inducing an oestrogen/androgen imbalance. Testicular, lung and other tumours secreting hCG lead to an overproduction of testicular oestrogens relative to androgen production. Supraphysiological stimulation of testicular steroidogenesis favours oestrogen over androgen production. This may also be observed in severe hypergonadotropic hypogonadism with highly elevated levels of luteinizing hormone. True hermaphroditism with ovarian oestrogen production may be a cause of increased oestrogen levels, but it is exceedingly rare and has usually been diagnosed earlier.

Gynaecomastia is observed in cases of deficient testosterone production. This may be due to primary testicular failure such as in Klinefelter’s syndrome, viral orchitis, trauma, or defects in testosterone biosynthesis. Primary testicular failure is associated with supranormal luteinizing hormone levels, leading to a higher oestrogen production relative to androgens. Hypogonadotropic hypogonadism, if severe, is usually not associated with gynaecomastia, since there is minimal testicular steroidogenesis with very low oestrogen production. If moderate, an imbalance between oestrogen/androgen production may be present. In cases of androgen receptor defects (so called androgen insensitivity) testosterone levels may be elevated but there is an impaired biological androgen action leading to an imbalance between oestrogen and effective androgen action on mammary tissue. Renal failure is characterized by a diminished testicular steroidogenesis. Initiation of growth hormone therapy has been found to induce gynaecomastia, probably since insulin-like growth factor-I reinforces the action of sex steroids (6).

The oestrogenic or antiandrogenic actions of a number of drugs are readily comprehensible. Oestrogen-containing cosmetics, digitalis, and phyto-oestrogens have feminizing effects. Other drugs that impair testosterone synthesis/action include: spironolactone, flutamide, cimetidine, ketaconazole, metronidazole, cisplatin, and alkylating agents. Of a larger number the mechanisms are not precisely known: isoniazid, methyldopa, calcium channel blockers, and captopril, tricyclic antidepressants. In fact, any drug taken may, in principle, be suspected to play a role. Also, antiretroviral treatment in cases of HIV infection may be associated with gynaecomastia (7).

Both physician and patient may overlook the use of dietary supplements, herbal medicine, and the like, as causative factors for gynaecomastia. It is becoming clear that some plants contain substances which have potent oestrogenic effects or inhibit 5α-reductase, the enzyme involved in the conversion of testosterone to its more potent form, 5α-dihydrotestosterone. The latter mechanism may undermine the inhibitory effect of androgens on the formation of breast tissue. Also, non-medical skin ointments, sometimes containing oestrogenizing substances, may be accountable.

It is not rare to find no good explanation for the occurrence of gynaecomastia. A transient feminizing state may have been present. Or, at tissue levels, there may be aromatization of androgen precursors to oestrogens, or there may be subtle endocrine derangements, not reflected in peripheral blood levels of oestrogens and/or androgens. Some imply environmental exposures to feminizing agents (‘endocrine disruptors’) as an explanation of gynaecomastia.

Galactorrhoea is rare, but may occur with relatively little breast formation. Prolactin is essential for milk secretion of the breast but does not produce growth of breasts. A prolactin secreting pituitary tumour may lead to suppression of gonadotropin production and thereby to decreased testicular androgen production, with a decreased inhibitory effect on the breast. Conversely, an oestrogen-producing tumour or oestrogenic compounds may induce an elevation of prolactin levels with similar effects.

Modern endocrine therapy of prostate carcinomas aims at maximal blockade of androgen effects on the prostate, and involves (pure) antiandrogenic drugs and gonadotropin releasing hormone agonists/antagonists. It is usually associated with a degree of (tender) gynaecomastia. Breast radiation before institution of the antiandrogenic treatment has been proven effective and has few complications (8). Also, the antioestrogen tamoxifen has appeared useful. In the early stages of hormonal treatment fat padding is not yet present. At that stage surgical removal of mammary glandular tissue may be an alternative prophylactic procedure. These preventive measures are adding to the acceptance of endocrine treatment of prostate cancer.

Gynaecomastia may be a primary breast tumour. A unilateral presentation, though usually a stage in the development of bilateral gynaecomastia, must arouse suspicion (9). It is usually painless, in contrast to gynaecomastia of recent onset. On palpation, the tissue is usually firm and irregular. There may be nipple dimpling. Axillary lymph nodes may be a sign of metastasis. Sonography, mammography and a biopsy are indicated to confirm the diagnosis (10). Long-standing gynaecomastia, such as in Klinefelter’s syndrome, may be a risk factor for development of breast cancer, though the chance is small. It has become clear that men with conditions of hypoandrogenism have a higher risk of developing breast carcinomas, probably since they are exposed to a high oestrogenic stimulus relative to the protective effect of androgens over a prolonged period. Androgen receptor mutations have been implicated in the development of breast cancers; their other clinical manifestations may be subtle (1, 3). The BRCA2 hereditary breast cancer mutation carries a higher risk, not only in women, but also in men.

Although it accounts for a small percentage of cases, clinical assessment must reasonably rule out a tumour as cause of gynaecomastia, which may be clinically suspected when the gynaecomastia is of recent and rapid onset, and if serum levels of hCG or oestrogens are high. A mass may be found in the abdomen or testis. The next issue is to identify whether there is an underlying endocrinopathy or whether it is idiopathic. Usually the patient’s history and physical examination provide leads. The history should encompass questions as to sexual differentiation and pubertal development, and other endocrine diseases/treatment. Hyperthyroidism and pituitary tumours or adrenal disease with an overproduction of adrenal androgens may all induce gynaecomastia. A painstaking inquiry as to drug use, medical and non-medical creams and ointments, alcohol and substance abuse, and exposure to environmental agents is mandatory (7). The patient may or may not be aware of liver/kidney disease.

The appropriate technique for physical examination to detect gynaecomastia is, with the patient in a supine position, pinching to see whether glandular tissue is present between thumb and fore-finger. Glandular tissue has a specific texture and resistance, and is usually not difficult to differentiate from fat issue.

Patients may complain of breast formation while on examination (almost) no glandular tissue is palpable; the area behind the areola mammae may contain fibrotic tissue or may be ‘empty’ as a result of resolution of glandular formations present earlier. The remaining fat pads may form the reason for the complaint. The endocrine mechanism behind the fat padding of the mammary gland is becoming increasingly understood. Oestrogenic stimulation of adipocytes and pre-adipocyte fibroblast cells leads to accumulation of fat in these cells.

Physical examination must further assess sexual development (signs of ambiguous sexual differentiation or hypogonadism), secondary sex characteristics, and careful examination of the testis, as to the presence of tumours, and signs and symptoms of liver disease or hyperthyroidism.

Further evaluation must be guided by the results of careful history taking and physical examination (1, 4). To exclude a malignancy, serum levels of hCG and α-fetoprotein may be determined. If plasma oestradiol levels are elevated this may provide a lead to the diagnosis of increased oestrogen production by a tumour or of enzymatic defects of adrenal steroidogenesis, but even in the presence of a (small) oestrogen-producing tumour they are not necessarily above the upper limit of normal values. The combination of the values of plasma levels of luteinizing hormone and testosterone may provide useful clues: low luteinizing hormone and low testosterone suggest hypopituitarism, or an overproduction of oestrogens; high luteinizing hormone and low testosterone are indicative of primary testicular causes, high luteinizing hormone and high testosterone point to androgen resistance or to an hCG-producing tumour since in most assays hCG cross-reacts with luteinizing hormone. Urinary 17-ketosteroids or plasma androstenedione and dehydroepiandrosterone are elevated if the adrenal is the source of precursors for aromatization to oestrogens. Liver and kidney function tests are usually easy to perform. If there are signs of endocrine disease such as hyperthyroidism, pituitary tumours or adrenal disease, appropriate laboratory investigations must be done. Depending on the findings of history and physical examination and first laboratory evaluation, additional testing may be indicated. Sonography of the testis may disclose the presence of tumours not detected by physical examination. Most adrenal masses will be visualized by CT or magnetic resonance imaging, as will liver tumours. Radiographic study of the chest may reveal a bronchial carcinoma, though they may be small.

If no abnormalities are found, as is frequently the case, a wait-and-see policy may be adopted by following the patient at intervals of 1–3 months. If the signs and symptoms show progression, there is reason for a more thorough assessment of possible aetiologies, such as tumours not easily detected by physical examination.

Since the aetiology of gynaecomastia encompasses such a wide range of causes, from totally innocent to potentially lethal, as in the case of a malignancy, treatment will be determined by the underlying cause. Malignancies require appropriate oncological treatment. Some forms of gynaecomastia, such as neonatal, pubertal, or occurring in old age (so-called physiological gynaecomastia) are usually self-limiting and for the most part require no treatment, provided there are no reasons for embarrassment. If drug-induced, use of the offending drug must be stopped; there are usually alternatives. For instance, omeprazole and ranitidine cause gynaecomastia less frequently than cimetidine.

Medical therapies are most effective during the active, proliferative phase of gynaecomastia, which is the first few months of its occurrence. However, most patients present themselves beyond this stage. Drug treatment is expected only to be successful for gynaecomastia of recent onset, before breast tissue has become fibrotic. In men with hypogonadism, testosterone administration may restore the oestrogen/androgen imbalance and may lead to improvement of the symptoms. The successes vary; it is usually not very satisfactory in men with Klinefelter’s syndrome. Testosterone administration increases the precursors of oestrogen synthesis, particularly in men with liver cirrhosis and obesity. There are reports in the literature of successes of administration of antioestrogenic treatment with oestrogen receptor antagonists such as clomiphene or tamoxifen, aromatase inhibitors such as anastrozole (11), and of dihydrotestosterone, which is a non-aromatizable androgen

In most cases of gynaecomastia it will turn out that there is no serious underlying pathology, particularly in puberty.

Though medically insignificant, gynaecomastia may have an impact on a person’s self-image. In particular, adolescents often view themselves through the eyes of their peers and constantly compare themselves with them. Any deviation in appearance may evoke peer ridicule and can result in low self-esteem, shame and stress; this may lead to withdrawal from social activities, and may impair healthy erotic and sexual development and interaction with others. Therefore, body image dissatisfaction must be addressed when a patient presents with gynaecomastia, even when gynaecomastia lacks medical significance. Reassurance that, based on medical examination, there are no relevant medical problems may not be sufficient. It may be even counterproductive in that the patient may feel that, in the absence of pathology, there is no room for discussing body image problems. It is rather the physician who must open discussion of these issues. Phrases like: ‘other persons with the same condition often experience discomfort with their bodies; how does that affect your life?’ may pave the way for an assessment of how patients experience their deviation from the norm. Modern techniques in plastic surgery allow removal of breast tissue on an outpatient basis and at reasonable cost; this deserves consideration when breast formation is disfiguring and damaging to a person’s self-confidence.

Surgical treatment is best performed by an experienced surgeon, because of the risks of unsightly scarring with contour irregularity, skin redundancy and formation of a saucer-shaped emptiness in place of the removed breast tissue, and malposition of the nipples. The surgical procedure depends on the anatomical situation encountered. An enlargement attributable to fibrous glandular tissue requires surgical excision. A fatty breast can often be treated with liposuction. The amount of sagging skin must be determined and excision of redundant skin may be considered (12). To avoid patient disillusionment it is best for endocrinologists to establish a working relationship with a surgeon interested in cosmetically acceptable results.