Gynecomastia: Etiology, Diagnosis, And Treatment
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 (13).
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 (38).
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).
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 (13). 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
(25,6).
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.
(21, 36). 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 (43). 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 (29). 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 (38). 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 (38). 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
(37). 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 (25, 16).
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. (39, 23). 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 histologic
changes similar to gynecomastia, an increase in estrogen and progesterone receptors
and an increase in downstream growth factors such as TGF-beta and bFGF (15).
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" (38).
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 (38). 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
(30). 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 (26).
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 (32). 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 (27). 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 (34, 14).
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 are benign,
but up to 10% are malignant. gynecomastia occurs in one third of cases, presumably
due to increased estrogen production (34).
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 (28).
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 alpha 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 (31).
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 (18, 44, 10). 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 which can then be aromatized peripherally to estradiol.
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). 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 (38).
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, an 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 (27). 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 (27). 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 (38). 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 which 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 (16).
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 (11, 3, 33). 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 which 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 (16, 9). 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 (17).
Refeeding gynecomastia refers to breast development in men recovering from
a malnourished state (13). 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
(27).
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, 12). 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 (16, 35). 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 (8).
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, 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 (40). 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 (27). Unfortunately, besides the drugs stated, a multitude
of others cause gynecomastia by unknown mechanisms (Table 3).
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
(19).
PATIENT EVALUATION
HISTORY AND PHYSICAL EXAMINATION
At presentation, all patients require a thorough history and physical exam.
Particular attention should be given to medications, drug and alcohol abuse,
as well as other chemical exposures. Symptoms of underlying systemic illness,
such as hyperthyroidism, liver disease, or renal failure should be sought. Furthermore,
the clinician must recall neoplasm as a possible etiology and should establish
the duration and timing of breast development. Obviously, rapid breast growth
that has occurred recently is more concerning than chronic gynecomastia. Additionally,
the clinician should inquire about fertility, erectile dysfunction and libido
to rule out hypogonadism, either primary or secondary, as a potential cause.
In our experience, the breast examination is best performed with the patient
supine and with the examiner palpating from the periphery to the areola. The
glandular mass should be measured in diameter. gynecomastia is diagnosed by
finding subareolar breast tissue of 2 cm in diameter or greater. Malignancy
is suspected if an immobile firm mass is found on physical examination. Skin
dimpling, nipple retraction or discharge, and axillary lymphadenopathy further
support malignancy as a possible diagnosis.
A thorough testicular exam is essential. Bilaterally small testes imply testicular
failure, while asymmetric testes or a testicular mass suggest the possibility
of neoplasm. Visual field impairment may suggest pituitary disease. Physical
findings of underlying systemic conditions such as thyrotoxicosis, HIV disease,
liver, or kidney failure should also be assessed.
LABORATORY EVALUATION
All patients who present with gynecomastia should have serum testosterone,
estradiol, LH and b HCG measured. Further testing should be tailored according
to the history, physical examination and the results of these initial tests.
An elevated b HCG or a markedly elevated serum estradiol suggests neoplasm and
a testicular ultrasound is warranted to identify a testicular tumor, keeping
in mind, however, that other non-testicular tumors can also secrete b HCG. A
low testosterone level, with an elevated LH and normal to high estrogen level
indicates primary hypogonadism. If the history suggests Klinefelter's Syndrome,
then a karyotype should be performed for definitive diagnosis. Low testosterone,
low LH and normal estradiol levels imply secondary hypogonadism, and hypothalamic
or pituitary causes should be sought. If testosterone, LH and estradiol levels
are all elevated, then the diagnosis of androgen resistance should be entertained.
Liver, kidney and thyroid function should be assessed if the physical examination
suggests liver failure, kidney failure, or hyperthyroidism, respectively. Furthermore,
if examination of breast tissue suggests malignancy, a biopsy should be performed.
This is of particular importance in patients with Klinefelter's syndrome, who
have an increased risk of breast cancer.
TREATMENT
Treatment of the underlying endocrinologic or systemic disease that has caused
gynecomastia is mandatory. Testicular tumors, such as Leydig cell, Sertoli cell
or granulosa cell tumors should be surgically removed. In addition to surgery,
germ cell tumors are further managed with chemotherapy involving cisplatin,
bleomycin and either vinblastine or etoposide (34, 14). Should underlying thyrotoxicosis,
renal or hepatic failure be discovered, appropriate therapy should be initiated.
Medications that cause gynecomastia should also be discontinued whenever possible
based on their role in management of the underlying condition. Of course, if
a breast biopsy indicates malignancy, then mastectomy should be performed.
If no pathologic abnormality is detected, then appropriate treatment is close
observation. A careful breast exam should be done initially every 3 months until
the gynecomastia regresses or stabilizes, after which a breast exam can be performed
yearly. It is important to remember that some cases of gynecomastia, especially
that which occurs in pubertal boys, can resolve spontaneously.
MEDICAL TREATMENT
If the gynecomastia is severe, does not resolve, and does not have a treatable
underlying cause, some medical therapies may be attempted. These include testosterone,
dihydrotestosterone, danazol, clomiphene citrate, tamoxifen and the aromatase
inhibitor testolactone. Testosterone treatment of hypogonadal men with gynecomastia
often fails to produce breast regression once gynecomastia is established. Unfortunately,
testosterone treatment may actually produce the side effect of gynecomastia
by being aromatized to estradiol. Thus, although testosterone is used to treat
hypogonadism, its use to specifically counteract gynecomastia is limited (42).
Dihydrotestosterone, a non-aromatizable androgen, has been used in patients
with prolonged pubertal gynecomastia with good response rates (22). Since dihydrotestosterone
is given either intramuscularly or percutaneously, this may restrict its usefulness.
Danazol, a weak androgen that inhibits gonadotropin secretion, resulting in
decreased serum testosterone levels, has been studied in a prospective placebo-controlled
trial, whereby gynecomastia resolved in 23 percent of the patients, as opposed
to 12 percent of the patients on placebo (20). Unfortunately, undesirable side
effects including edema, acne, and cramps have limited its use (27). Investigators
have reported a 64 percent response rate with 100 mg/day of clomiphene citrate,
a weak estrogen and moderate antiestrogen (24). Lower doses of clomiphene have
shown varied results, indicating that higher doses may need to be administered,
if clomiphene is to be attempted. tamoxifen, also an antiestrogen, has been
studied in 2 randomized, double-blind studies in which a statistically significant
regression in breast size was achieved, although complete regression was not
documented (1). One study compared tamoxifen with danazol in the treatment of
gynecomastia. Although patients taking tamoxifen had a greater response with
complete resolution in 78 percent of patients treated with tamoxifen, as compared
to only a 40 percent response in the danazol-treated group, the relapse rate
was higher for the tamoxifen group (41). Although complete breast regression
may not be achieved and a chance of recurrence exists with therapy, tamoxifen,
due to relatively lower side effect profile, may be a more reasonable choice
when compared to the other therapies. If used, tamoxifen should be given at
a dose of 10 mg twice a day for at least 3 months (27). An aromatase inhibitor,
testolactone, has also been studied in an uncontrolled trial with promising
effects (45). Further studies must be performed on this drug before any recommendations
can be established on its usefulness in the treatment of gynecomastia.
SURGICAL TREATMENT
When medical therapy is ineffective, particularly in cases of longstanding
gynecomastia, or when the gynecomastia interferes with the patient's activities
of daily living, then surgical therapy is appropriate. This includes removal
of glandular tissue coupled with liposuction, if needed. In our experience,
uses of delicate cosmetic surgical techniques are warranted to prevent unsightly
scarring.
SUMMARY
In summary, gynecomastia is a relatively common disorder. The causes of its
development range vastly from benign physiologic processes to rare neoplasms.
Thus, in order to properly diagnose the etiology of the gynecomastia, the clinician
must understand the hormonal factors involved in breast development. Parallel
to female breast development, estrogen, along with GH and IGF-1 is required
for breast growth in males. Since a balance exists between estrogen and androgens
in males, any disease state or medication that can increase circulating estrogen
or decrease circulating androgen, causing an elevation in the estrogen to androgen
ratio, can induce gynecomastia. Due to the diversity of possibly etiologies,
including neoplasm, performing a careful history and physical is imperative.
Once gynecomastia has been diagnosed, treatment of the underlying cause is warranted.
If no underlying cause is discovered, then close observation is appropriate.
If the gynecomastia is severe, however, medical therapy can be attempted and
if ineffective, glandular tissue can be removed surgically.
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