GYNECOMASTIA: ETIOLOGY, DIAGNOSIS, AND TREATMENT
Chapter 14 - Ronald S. Swerdloff, MD, Jason Ng, MD, and Gladys E. Palomeno, MD,
March 1, 2004 Index



INTRODUCTION
This chapter will review: the ontogeny and physiology of breast development; factors that influence breast enlargement in the male; the differential diagnosis of gynecomastia; the process of diagnostic investigation; and treatment of gynecomastia.

BREAST DEVELOPMENT

Male breast development occurs in an analogous fashion to female breast development. At puberty in the female breast, complex hormonal interplay occurs resulting in growth and maturation of the adult female breast.

In early fetal life, epithelial cells, derived from the epidermis of the area programmed to later become the areola, proliferate into ducts, which connect to the nipple at the skin's surface. The blind ends of these ducts bud to form alveolar structures in later gestation. With the decline in fetal prolactin, placental estrogen and progesterone at birth, the infantile breast regresses until puberty (15).

During thelarche, the initial clinical appearance of the breast bud, growth and division of the ducts occur, eventually giving rise to club-shaped terminal end buds, which then form alveolar buds. Approximately a dozen alveolar buds will cluster around a terminal duct, forming the type 1 lobule. Eventually, the type 1 lobule will mature into types 2 and 3 lobules, called ductules, by increasing its number of alveolar buds to as many as 50 in type 2 and 80 in type 3 lobules. The entire differentiation process takes years after the onset of puberty and, if pregnancy is not achieved, may never be completed (42).

HORMONAL REGULATION OF BREAST DEVELOPMENT

The initiation and progression of breast development involves a coordinated effort of pituitary and ovarian hormones, as well as local mediators (see Figure 1).



ESTROGEN, GH AND IGF-1, PROGESTERONE, & PROLACTIN

Estrogen and progesterone act in an integrative fashion to stimulate normal adult female breast development. Estrogen, acting through its ER a receptor, promotes duct growth, while progesterone, also acting through its receptor (PR), supports alveolar development (15). This is demonstrated by experiments in ER a knockout mice which display grossly impaired ductal development, whereas the PR knockout mice possess significant ductal development, but lack alveolar differentiation (28,6).

Although estrogens and progestogens are vital to mammary growth, they are ineffective in the absence of anterior pituitary hormones (13). Thus, neither estrogen alone nor estrogen plus progesterone can sustain breast development without other mediators, such as GH and IGF-1, as confirmed by studies involving the administration of estrogen and GH to hypophysectomized and oophorectomized female rats, which resulted in breast ductal development. The GH effects on ductal growth are mediated through stimulation of IGF-1. This is demonstrated by studies of estrogen and GH administration to IGF-1 knockout rats that showed significantly decreased mammary development when compared to age-matched IGF-1- intact controls. Combined estrogen and IGF-1 treatment in these IGF-1 knockout rats restored mammary growth. (23, 40). In addition, Walden et al. demonstrated that GH-stimulated production of IGF-1 mRNA in the mammary gland itself, suggesting that IGF-1 production in the stromal compartment of the mammary gland acts locally to promote breast development (49). Furthermore, other data indicates that estrogen promotes GH secretion and increased GH levels, stimulating the production of IGF-1, which synergizes with estrogen to induce ductal development.

Like estrogen, progesterone has minimal effects in breast development without concomitant anterior pituitary hormones; again indicating that progesterone interacts closely with pituitary hormones. For example, prolonged treatment of dogs with progestogens such as depot medroxyprogesterone acetate or with proligestone caused increased GH and IGF-1 levels, suggesting that progesterone may also have an effect on GH secretion (33). In addition, clinical studies have correlated maximal cell proliferation to specific phases in the female menstrual cycle. For example, maximal proliferation occurs not during the follicular phase when estrogens reach peak levels and progesterone is low (less than 1 ng/mL [3.1nmol}), but rather, it occurs during the luteal phase when progesterone reaches levels of 10-20 ng/mL (31- 62nmol) and estrogen levels are two to three times lower than in the follicular phase (42). Furthermore, immunohistochemical studies of ER and PR showed that the highest percentage of proliferating cells, found almost exclusively in the type 1 lobules, contained the highest percentage of ER and PR positive cells (42). Similarly, there is immunocytological presence of ER, PR, and androgen receptors (AR) in gynecomastia and male breast carcinoma. ER, PR and AR expression was observed in 100% (30/30) of gynecomastia cases (41). Given these data and the fact that PR knockout mice lack alveolar development in breast tissue, it appears as if progesterone, analogous to estrogen, may increase GH secretion and act through its receptor on mammary tissue to enhance breast development, specifically alveolar differentiation (28, 18).

Prolactin is another anterior pituitary hormone integral to breast development. Prolactin is not only secreted by the pituitary gland but may be produced in normal mammary tissue epithelial cells and breast tumors. (44, 25). Prolactin stimulates epithelial cell proliferation only in the presence of estrogen and enhances lobulo-alveolar differentiation only with concomitant progesterone.

ANDROGEN AND AROMATASE

Estrogen effects on the breast may be the result of either circulating estradiol levels or locally produced estrogens. Aromatase P450 catalyzes the conversion of the C19 steroids, androstenedione, testosterone, and 16-a-hydroxyandrostenedione to estrone, estradiol-17b and estriol. As such, an overabundance of substrate or an increase in enzyme activity can increase estrogen concentrations and thus initiate the cascade to breast development in females and males. For example, in the more complete forms of androgen insensitivity syndromes in genetically male (XY) patients, excess androgen aromatizes into estrogen resulting in not only gynecomastia, but also a phenotypic female appearance. Furthermore, the biologic effects of over expression of the aromatase enzyme in female and male mice transgenic for the aromatase gene result in increased breast proliferation. In female transgenetics, over expression of aromatase promotes the induction of hyperplastic and dysplastic changes in breast tissue. Over expression of aromatase in male transgenics caused increased mammary growth and histological changes similar to gynecomastia, an increase in estrogen and progesterone receptors and an increase in downstream growth factors such as TGF-beta and bFGF (17). Interestingly, treatment with an aromatase inhibitor leads to involution of the mammalian gland phenotype (27). Thus, although androgens do not stimulate breast development directly, they may do so if they aromatize to estrogen. This occurs in cases of androgen excess or in patients with increased aromatase activity.

PHYSIOLOGIC GYNECOMASTIA

Gynecomastia, breast development in males, can occur normally during three phases of life. The first occurs shortly after birth in both males and females. This is caused by the high levels of estradiol and progesterone produced by the mother during pregnancy, which stimulates newborn breast tissue. It can persist for several weeks after birth and can cause mild breast discharge called "witch's milk" (42).Puberty marks the second situation in which gynecomastia can occur physiologically. In fact, up to 60% of boys have detectable gynecomastia by age 14. Although it is mostly bilateral, it can occur unilaterally, and usually resolves within 3 years of onset (42).

Interestingly, in early puberty, the pituitary gland releases gonadotropins in order to stimulate testicular production of testosterone mostly at nighttime. Estrogens, however, rise throughout the entire day. Some studies have shown that a decreased androgen to estrogen ratio exists in boys with pubertal gynecomastia when compared with boys who do not develop gynecomastia (34). Furthermore, another study showed increased aromatase activity in the skin fibroblasts of boys with gynecomastia. Thus, the mechanism by which pubertal gynecomastia occurs may be due to either decreased production of androgens or increased aromatization of circulating androgens, thus increasing the estrogen to androgen ratio (29).

The third age range in which gynecomastia is frequently seen is during older age (>60 years). Although the exact mechanisms by which this can occur have not been fully elucidated, evidence suggests that it may result from increased peripheral aromatase activity secondary to the increase in total body fat, coupled with mild hypogonadism associated with aging. For instance, investigators have shown increased urinary estrogen levels in obese individuals, and have demonstrated aromatase expression in adipose tissue (36). Thus, like the gynecomastia of obesity, the gynecomastia of aging may partly result from increased aromatase activity, causing increased circulating estrogen levels (7). Moreover, not only does total body fat increase with age, but there may be an increase in aromatase activity in the adipose tissue already present, increasing circulating estrogens even further. Lastly, SHBG increases with age in men. Since SHBG binds estrogen with less affinity than testosterone, the bioavailable estradiol to bioavailable testosterone ratio may increase in the obese older male.

PATHOLOGIC GYNECOMASTIA

INCREASED ESTROGEN

Since the development of breast tissue in males occurs in an analogous manner to that in females, the same hormones that affect female breast tissue can cause gynecomastia. The testes secrete only 6-10 mg of estradiol and 2.5 mg of estrone per day. Since this only comprises a small fraction of estrogens in circulation (i.e. 15% of estradiol and 5% of estrone), the remainder of estrogen in males is derived from the extraglandular aromatization of testosterone and androstenedione to estradiol and estrone, respectively (30). Thus, any cause of estrogen excess from overproduction to peripheral aromatization of androgens can initiate the cascade to breast development.

TUMORS

Testicular tumors can lead to increased blood estrogen levels by: estrogen overproduction; androgen overproduction with aromatization in the periphery to estrogens; and by ectopic secretion of gonadotropins which stimulate otherwise normal Leydig cells. Tumors causing an overproduction of estrogen represent an unusual but important cause of estrogen excess. Examples of estrogen-secreting tumors include: Leydig cell tumors, Sertoli cell tumors, granulosa cell tumors and adrenal tumors.

Interstitial cell tumors, or Leydig cell tumors constitute 1%-3% of all testis tumors. Usually, they occur in men between the ages of 20 and 60, although up to 25% of them occur prepubertally. In prepubertal cases, isosexual precocity, rapid somatic growth, and increased bone age with elevated serum testosterone and urinary 17-ketosteroid levels are the presenting features. In adults, elevated estrogen levels coupled with a palpable testicular mass and gynecomastia may develop. Though mostly benign, Leydig cell tumors may be malignant and metastasize to lung, liver, and retroperitoneal lymph nodes (38, 16).

Sertoli cell tumors comprise less than 1% of all testicular tumors and occur at all ages, but one third have occurred in patients less than 13 years, usually in boys under 6 months of age. Although they arise in young boys, they usually do not produce endocrinologic effects in children. Again, the majority is benign, but up to 10% is malignant. Gynecomastia occurs in one third of cases, presumably due to increased estrogen production (38).

Granulosa cell tumors, which occur very rarely in the testes, can also overproduce estrogen. In fact, only eleven cases have been reported with gynecomastia as a presenting feature in half of them (31).

Germ cell tumors are the most common cancer in males between the ages of 15 and 35. They are divided into seminomatous and nonseminomatous subtypes and include embryonal carcinoma, yolk sac carcinoma, choriocarcinoma and teratomas. Elevated a fetoprotein (AFP) and b HCG function as reliable markers in some tumors. As a result of the increased b HCG, acting analogously to LH to stimulate the Leydig cell LH receptor, testicular estrogen production is also increased, which, in turn, can cause gynecomastia. Although germ cell tumors generally arise in the testes, they can also originate extra-gonadally, specifically in the mediastinum. These extragonadal tumors also possess the capability of producing b HCG, but they must be differentiated from a multitude of other tumors such as large cell carcinomas of the lung which can synthesize ectopic b HCG (35).

Some neoplasms that overproduce estrogens also possess aromatase overactivity. Sertoli Cell tumors in boys with Peutz-Jegher syndrome, an autosomal dominant disease characterized by pigmented macules on the lips, gastrointestinal polyposis and hormonally active tumors in males and females, for instance, have repeatedly demonstrated aromatase overactivity, resulting in gynecomastia, rapid growth and advanced bone age as presenting features (20, 50, 12). Feminizing Sertoli cell tumors with increased aromatase activity can also be seen in the Carney complex, an autosomal dominant disease characterized by cardiac myxomas, cutaneous pigmentation, adrenal nodules and hypercortisolism. Other than sex-cord tumors, fibrolamellar hepatocellular carcinoma has also been shown to possess ectopic aromatase activity, causing severe gynecomastia in a 17-year-old boy (2). Furthermore, adrenal tumors can secrete excess dehydroepiandrosterone (DHEA), DHEA-sulfate (DHEAS) and androstenedione that can then be aromatized peripherally to estradiol.

Table 1.
Tumor type .........Hormone produced ......Aromatase overactivity
Leydig cell tumor ....testosterone
Sertoli cell tumor ....Estrogen + ...............(in Peutz-Jegher Syndrome)
.................................................. .......+ (in Carney complex)
Germ cell tumor ......b HCGestrogen
Granulosa cell tumor Estrogen
Adrenal tumors ..Dehydroepiandrosterone(DHEA)
.......................dehydroepiandrosterone-sulfate
.......................( DHEA-S), andandrostenedione
.......................which are converted in the
.......................periphery to estrogens.

NON-TUMOR CAUSES OF ESTROGEN EXCESS

INCREASED AROMATASE ACTIVITY

Besides tumors, other conditions have been associated with excessive aromatization of testosterone and androgens to estrogen, which results in gynecomastia. For instance, a familial form of gynecomastia has been discovered, in which affected family members have an elevation of extragonadal aromatase activity (5). More recently, novel gain-of-function mutations in chromosome 15 have been reported to cause gynecomastia, possibly by forming cryptic promoters that lead to over expression of aromatase. (43). As stated, obesity may cause estrogen excess through increased aromatase activity in adipose tissue. Furthermore, hyperthyroidism induces gynecomastia through several mechanisms, including increased aromatase activity (42).

DISPLACEMENT OF ESTROGENS FROM SHBG

Another cause of gynecomastia from estrogen excess includes steroid displacement from sex-hormone binding globulin (SHBG). SHBG binds androgens more avidly than estrogen. Thus, any condition or drug that can displace steroids from SHBG, will more easily displace estrogen, allowing for higher circulating levels of estrogen. Drugs can cause gynecomastia by numerous mechanisms besides displacement from SHBG. These drugs and their mechanisms will be addressed in a subsequent section.

DECREASED TESTOSTERONE AND ANDROGEN RESISTANCE

Breast development requires the presence of estrogen. Androgens, on the other hand oppose the estrogenic effects. Thus, equilibrium exists between estrogen and androgens in the adult male to prevent growth of breast tissue, whereby either an increase in estrogen or a decrease in androgen can tip the balance toward gynecomastia. Increased estrogen levels will increase glandular proliferation by several mechanisms. These include direct stimulation of glandular tissue and by suppressing LH, therefore decreasing testosterone secretion by the testes and exaggerating the already high estrogen to androgen ratio.

Besides increased estrogen production, decreased testosterone levels can cause an elevation in the estrogen to androgen ratio, producing gynecomastia. Primary hypogonadism, with its reduction in serum testosterone and increased serum LH levels increases testicular estradiol production and is associated with an increased estrogen to androgen ratio. Klinefelter's syndrome, occurring in 1 in 500 males who possess an XXY karyotype and primary testicular failure, features gynecomastia as well, again presumably secondary to decreased testosterone production, compensatory increased LH secretion, overstimulation of the Leydig cells and relative estrogen excess. In addition, any acquired testicular disease resulting in primary hypogonadism such as viral and bacterial orchitis, trauma, or radiation can also promote gynecomastia by the same mechanisms (30). Lastly, enzyme deficiencies in the testosterone synthesis pathway from cholesterol also result in depressed testosterone levels and hence a relative increase in estrogen. Deficiency of 17-oxosteroid reductase, the enzyme that catalyzes the conversion of androstenedione to testosterone and estrone and estrone to estradiol, for example, will cause elevation in estrone and androstenedione, which is then further aromatized to estradiol (7).

Secondary hypogonadism, if severe enough, results in low serum testosterone and unopposed estrogen effect from increased conversion of adrenal precursors to estrogens (30). Thus, patients with Kallmann's syndrome, a form of congenital secondary hypogonadism with anosmia, also develop gynecomastia. In fact, hypogonadism from whatever cause constitutes most cases of gynecomastia.

The androgen resistance syndromes, including complete and partial testicular feminization (e.g. Reifenstein's syndrome) are characterized by gynecomastia and varying degrees of pseudohermaphroditism. Kennedy Syndrome, a neurodegenerative disease, is also associated with decreased effective testosterone due to a defective androgen receptor (42). The gynecomastia is the combined result of decreased androgen responsiveness at the breast level and increased estrogen levels as a result of elevated androgen precursors of estradiol and estrone. As such, androgens in these diseases are not recognized by the peripheral tissues including the breast and pituitary. Androgen resistance at the pituitary results in elevated serum LH levels and increased circulating testosterone. The increased serum testosterone is then aromatized peripherally, promoting gynecomastia. Thus, gynecomastia is the result of increased estradiol levels that arise due to unopposed androgen unresponsiveness.

OTHER DISEASES

Other disease states have also resulted in gynecomastia.

Men with end stage renal disease may have reduced testosterone, and elevated gonadotropins. This apparent primary testicular failure may then lead to increased breast development (18).

The gynecomastia of liver disease, particularly cirrhosis, does not have a clear etiology. Some have speculated that the gynecomastia is the result of estrogen overproduction, possibly secondary to increased extraglandular aromatization of androstenedione, which may have decreased hepatic clearance in cirrhotics. However, testosterone administration to cirrhotics causes a rise in estradiol, but decreases the prevalence of gynecomastia (13, 3, 37). Therefore, although the association of gynecomastia with liver disease is apparent, current data are conflicting and the mechanism by which this occurs remains unclear.

As previously stated, thyrotoxicosis is associated with gynecomastia. Patients often have elevated estrogen that may result from a stimulatory effect of thyroid hormone on peripheral aromatase. Testosterone may also be increased possibly due to thyroid-hormone-stimulated increase in SHBG, as free testosterone is usually normal. Since SHBG binds testosterone more avidly than estradiol, there is a higher ratio of free estradiol to free testosterone. Thus, with normal testosterone and increased estrogen, there is an elevated estrogen to testosterone ratio. In addition, LH is also increased, which may also stimulate testicular estrogen synthesis (18, 10).

Gynecomastia can also follow spinal cord disorders. Most patients with spinal cord disorders display depressed testosterone levels and, in fact, can develop testicular atrophy with resultant hypogonadism and infertility. Some have speculated that this may result from recurrent urinary tract infections, increased scrotal temperature, and a neuropathic bladder, which ultimately cause acquired primary testicular failure. The exact mechanism, however, remains elusive (19).

Refeeding gynecomastia refers to breast development in men recovering from a malnourished state (15). Although most cases regress within seven months, the etiology of this phenomenon has not been fully elucidated.

HIV patients can also develop gynecomastia. There is a high incidence of androgen deficiency due to multifactorial causes, including primary and secondary hypogonadism (30).

DRUGS

A significant percentage of gynecomastia is caused by medications or exogenous chemicals that result in increased estrogen effect. This may occur by several mechanisms: 1) they possess intrinsic estrogen-like properties, 2) they increase endogenous estrogen production, or 3) they supply an excess of an estrogen precursor (e.g. testosterone or androstenedione) which can be aromatized to estrogen. Examples of drugs that cause gynecomastia are listed in Tables 2 and 3. Contact with estrogen vaginal creams, for instance, can elevate circulating estrogen levels. These may or may not be detected by standard estrogenic qualitative assays. An estrogen-containing embalming cream has been reported to cause gynecomastia in morticians (4, 14). Recreational use of marijuana, a phytoestrogen, has also been associated with gynecomastia. It has been suggested that digitalis causes gynecomastia due to its ability to bind to estrogen receptors (18, 39). The appearance of gynecomastia has been described in body builders and athletes after the administration of aromatizable androgens. The gynecomastia was presumably caused by an excess of circulating estrogens due to the conversion of androgens to estrogen by peripheral aromatase enzymes (9).

Drugs and chemicals that cause decreased testosterone levels either by causing direct testicular damage, by blocking testosterone synthesis, or by blocking androgen action can produce gynecomastia. For instance, phenothrin, a chemical component in delousing agents, possessing antiandrogenic activity, has been attributed as the cause of an epidemic of gynaecomastia among Haitian refugees in US detention centers in 1981 and 1982 (8). Chemotherapeutic drugs, such as alkylating agents, cause Leydig cell and germ cell damage, resulting in primary hypogonadism. Flutamide, an anti-androgen used as treatment for prostate cancer, blocks androgen action in peripheral tissues, while cimetidine blocks androgen receptors. Ketoconazole, on the other hand, can inhibit steroidogenic enzymes required for testosterone synthesis. Spironolactone causes gynecomastia by several mechanisms. Like ketoconazole, it can block androgen production by inhibiting enzymes in the testosterone synthetic pathway (i.e. 17a hydroxylase and 17-20-desmolase), but it can also block receptor-binding of testosterone and dihydrotestosterone (45). In addition to decreasing testosterone levels and biologic effects, Spironolactone also displaces estradiol from SHBG, increasing free estrogen levels. Ethanol increases the estrogen to androgen ratio and induces gynecomastia by multiple mechanisms as well. Firstly, it is associated with increased SHBG, which decreases free testosterone levels. Secondly, it increases hepatic clearance of testosterone, and thirdly, it has a direct toxic effect on the testes themselves (30). Unfortunately, besides the drugs stated, a multitude of others cause gynecomastia by unknown mechanisms (Table 3).


Table 2. Drugs that induce gynecomastia by known mechanisms
Estrogen-
like, or binds to estrogen receptor Stimulate estrogen synthesis Supply aromatizable estrogen precursors Direct Testicular Damage Block testosterone synthesis Block androgen action Displace estrogen from SHBG
Estrogen vaginal cream Gonado-
tropins Exogenous androgen Busulfan Ketoconazole Flutamide Spironol-
actone
Estrogen-
containing embalming cream Growth Hormone Androgen precursors (ie androstene-
dione and DHEA) Nitrosurea Spironol-
actone Bicalut-
amide Ethanol
Delousing powder Vincristine Metronidazole finasteride
Digitalis Ethanol Etomidate Cyproterone
clomiphene Zanoterone
Marijuana Cimetidine
Ranitidine
Spironol-
actone



Table 3. Drugs that cause gynecomastia by uncertain mechanisms:
Cardiac and antihypertensive medications:
Calcium channel blockers (verapamil, nifedipine, diltiazem)
ACE Inhibitors (captopril, enalapril
b blockers
Amiodarone
Methyldopa
Reserpine
Nitrates

Psychoactive drugs:
Neuroleptics
Diazepam
Neuroleptics
Diazepam
Phenytoin
Tricyclic antidepressants
Haloperidol


Drugs for infectious diseases:
Indinavir
Isoniazid
Ethionamide
Griseofulvin

Drugs of Abuse:
amphetamines

Other:
Theophylline
Omeprazole
Auranofin
Diethylpropion
Domperidone
Penicillamine
Sulindac
Heparin


MALE BREAST CANCER

Male breast cancer is rare and comprises only 0.2 percent of all male cancers. Although uncommon, it has been associated with gynecomastia and necessitates inclusion in the differential diagnosis. Other risks include Klinefelter's syndrome, exogenous estrogen exposure, family history, and testicular disorders. It is unclear if these are specific risks for breast cancer are linked to the stimulatory process responsible for gynecomastia. New evidence suggests obesity and consumption of red meat may also raise the risk for the development of male breast cancer (21).