Gynecomastia

To the Editor: In the August and November 2009 issues of Mayo Clinic Proceedings, Haynes and Mookadam¹ published a Medical Image entitled “Male Gynecomastia” and Johnson and Murad² published a Concise Review for Clinicians entitled “Gynecomastia: Pathophysiology, Evaluation, and, Management,” respectively. In response to these publications, I appreciate the journal's Editorial Board providing me an opportunity to comment on a standardized method for detecting, defining, and quantifying palpable breast tissue (PBT) in men, as well as to discuss the general prevalence of PBT, potential etiologies, and indications for further evaluation.

Incidentally, I suggest that the term palpable breast tissue be used instead of gynecomastia because the presence of breast tissue is a normal finding in men. Gynecomastia literally refers to the presence of a female breast in men.

Until 1979, breast tissue was considered to develop during puberty in some boys and then to regress and to be rare in men. Indeed, in the excellent review of the pathogenesis of gynecomastia in 1980 by Wilson et al,³ the authors reported that “in normal adult man, no breast tissue can be palpated.” They also stated that “it is possible that gynecomastia, if it occurs at all in elderly men, is rare.” Thus, when breast tissue was identified in men, it was considered pathologic, that is, to be an adverse effect of numerous different medications or to be due to the onset of a hormonal imbalance induced by an underlying malignancy or other serious disease state affecting sex hormone production.

The method in which gynecomastia was diagnosed often was unclear. Frequently, a painful or tender breast was confused with the presence of gynecomastia, that is, with the mere presence of any PBT. Also, commonly the presence of pain and/or tenderness was considered to represent new-onset gynecomastia, although data were often lacking to document this. A painful breast, ie, mastodynia and/or breast tenderness, generally is a self-limiting condition of unknown etiology. Acute onset of breast enlargement associated with mastodynia likely represents an inflammatory process of unknown etiology, at least in some patients.⁴ In any regard, these conditions do not require further investigation other than possibly determination of serum estradiol, luteinizing hormone (LH), and β-human chorionic gonadotropin concentrations.

When PBT is first noted by the patient or health care professional, regardless of whether pain and/or tenderness is present, commonly a mammogram is ordered. This is indicated only if the PBT is clearly of recent onset, very firm, irregular, and unilateral and particularly if associated with skin retraction, ie, with clinical suspicion of malignancy, a very rare occurrence.⁵

In 1979, I published a report indicating that PBT was present in 36% of healthy young and middle-aged fertile men.⁶ It was asymptomatic and generally had not been noticed by these men. This high prevalence has subsequently been documented by others.⁷

The method I used to identify and quantify the amount of breast tissue present was not indicated in detail.⁶ However, it was explicitly explained subsequently in an article authored by my former research fellow, Niewoehner, and me.⁸ An illustration of the procedure was presented in a review article by Braunstein⁹ in the New England Journal of Medicine. A summary of the technique follows.

The presence of PBT is defined as a palpable discrete disc of firm homogeneous, subareolar breast tissue at least 2 cm in diameter. It is measured as follows: with a finger at the superior inner quadrant and thumb at the inferior outer quadrant, a pincerlike movement is made to pick up a firm disc of breast tissue from the chest wall, the diameter of which is then measured with a flexible rule. Somewhat arbitrarily, if the tissue is smaller than 2 cm, gynecomastia (PBT) was considered not to be present. The limit of 2 cm was chosen to ensure the presence of PBT. Breast tissue is composed of stroma and ductal structures as well as fat; thus, the density of breast tissue is greater than that of fat. If breast firmness cannot be differentiated from fat tissue, the consistency of fat tissue itself can be determined by compression of the axillary fold using the same technique.¹⁰ This methodology has been performed by others.^7,11-13

In the article that Niewoehner and I wrote,⁸ we demonstrated that the prevalence of PBT increased with age and adiposity. In older men, the mean was 65% but was as high as 85% in those with a body mass index (calculated as the weight in kilograms divided by height in meters squared) greater than 25.

The increase in the prevalence of PBT with aging has been attributed to the relative and absolute increase in fat mass with aging, and thus an increase in fat cell steroid aromatase activity. This in turn results in an increase in estrogen production,^8,10 a plausible but not proven mechanism.

Although numerous drugs have been implicated in the genesis of gynecomastia, most articles are case reports, and others are poorly documented. Of medications currently in use, only spironolactone, possibly cimetadine,¹⁴ and estrogens have been clearly shown to induce breast enlargement. In addition, spironolactone-induced breast enlargement is dose dependent.^15,16 Furthermore, PBT (gynecomastia) is so common it would be difficult to ascribe the gynecomastia to a medication unless a randomized control trial or rechallenge test were performed.

In my opinion, the presence of PBT does not require an evaluation for thyroid, liver, primary, hypothalamic, or pituitary gonadal abnormalities. Also, if estrogen production is increased, an evaluation for malignancies is not indicated unless the PBT clearly is new and/or progressive.

Incidentally, to my knowledge, hyperthyroidism has not been shown to be a pathologically important cause of gynecomastia. Although thyrotoxicosis can induce changes in sex hormone concentrations,¹⁷ the prevalence of gynecomastia in these patients is similar to that in the general population. Nevertheless, and regardless of the potential etiology, if breast enlargement is bilateral and clearly of recent onset or is progressive, a potential etiological evaluation should be considered, beginning with determination of estradiol, LH, and β-human chorionic gonadotropin concentrations, as indicated previously.

A low circulating testosterone concentration, particularly in the setting of a normal estradiol concentration, has been suggested to result in gynecomastia. However, to my knowledge, an enlargement in breast tissue mass secondary to a loss of inhibition by testosterone, allowing an estrogen stimulatory effect to be expressed by a normal, unchanged estrogen concentration, has not been documented. In addition, estrogen is a potent inhibitor of LH secretion in men. In many cases in which an estrogen-testosterone ratio is high and is due to a low or low-normal testosterone concentration, the decreased testosterone could be due to a modest increase in estrogen concentration resulting in feedback inhibition of LH.¹⁸ In this context, an increase in breast mass would be due to the elevation in estrogen concentration, not the result of a low testosterone value, per se.

In summary, PBT is common in men, increases with age and/or adiposity, and is rarely due to commonly used medications unless they increase the circulating estradiol concentration or produce an estrogen-mimetic substance. A hormonal evaluation is unnecessary unless the observed breast enlargement is clearly of recent origin or is increasing. Mammography is never indicated unless there is a strong clinical suspicion of a breast malignancy. Finally, before the publication by Niewoehner and me,⁸ a standardized assessment of the presence of gynecomastia often was not clearly defined. Many of the medication-associated reports appeared earlier, and the detection methodology was not described, thus complicating an interpretation of the data.

On the basis of the observed high prevalence of PBT in the general male population, implication of a medication in the genesis of gynecomastia will require a large population-based study or knowledge that PBT was not present before introduction of that medication into a treatment regimen. Preferably, a rechallenge test also should be performed to document a cause-and-effect relationship.