Gynecomastia

Definition
 
Gynecomastia is a common disease of the male breast where
there is a benign glandular enlargement of that breast at
some time in the male's life. It usually consists of the
appearance of a flat pad of glandular tissue beneath a
nipple which becomes tender at the same time. The
development may be unilateral or bilateral. There is rarely
a continued growth of the breast tissue; ordinarily the
process is of brief duration and stops short of the
production of permanent enlargement of the breast. 

Causes
 
A great number of patients who suffer from this disease
have a disturbance in the proper ratio of androgen and
estrogen levels. The normal ratio of the two hormones in
plasma is approximately 100:1. "The etiology of
gynecomastia in patients with a known documented cause
appears to be related to increased estrogen stimulation,
decreased testosterone levels, or some alteration of the
estrogens and androgen so that the androgen-estrogen ratio
is decreased"(Williams 373). From this information it was
discovered that there is also a lower ratio of weaker
adrenal androgens (delta 4-androstenedione and
dehydroepiandrosterone) found in youths with this disease.
It was once believed that there was an imbalance in the
ratios of testosterone to estrogen or estradiol, but this
is now know to be untrue.
 
There are three areas the can be attributed to the cause of
gynecomastia: physiologic, pathologic and pharmacologic.
"Enlargement of the male breast can be a normal physiologic
phenomenon at certain stages of life or the result of
several pathologic states."(Isselbacher, 2037) 

In the case of physiologic gynecomastia the disease can
occur in a newborn baby, at puberty or at any time in a
man's life. In the newborn, transient enlargement of the
breast is due to the action of maternal and/or placental
estrogens. The enlargement usually disappears within a few
weeks. Adolescent gynecomastia is common during puberty
with the onset at the median age of 14. It is often
asymmetrical and frequently tender. It regresses so that by
the age of 20 only a small number of men have palpable
vestiges of gynecomastia in one or both the breasts.
Gynecomastia of aging also occurs in otherwise healthy men.
Forty percent or more of aged men have gynecomastia. One
explanation is the increase in age in the conversion of
androgens to estrogens in extra-glandular tissues. Drug
therapy and abnormal liver functioning can also be causes
of gynecomastia in older men.
 
When the disease is pathologic, the patient can have
increased estrogen secretions, increased conversion of
androgens to estrogens, or decreased androgen activity due
to a failure in protein receptors. Increased estrogen
secretions are found in such diseases and disorders as
Hermaphroditism, Kleinfelter's syndrome, congenital adrenal
hyperlasia, and adrenal carcinoma or testicular tumors. In
the second case some examples are adrenal carcinoma, liver
disorders, malnutrition and thyroidtoxicosis. Decreased
androgen activity can be found in complete testicular
feminization, incomplete testicular feminization and
Reifenstein's syndrome.
 
Many drugs can cause gynecomastia by several mechanisms.
The drugs can either act directly as estrogens or cause and
increase in plasma estrogen levels. "Boys and young men are
particularly sensitive to estrogen, and can develop
gynecomastia after the use of dermal ointments containing
estrogen or after the ingestion of milk or meat from
estrogen-treated animals."(Isselbacher, 2038) 

Some examples of drugs that may have cause gynecomastia
include Cannabinoids (methane and marijuana), Psychotropics
(pheno-thiazine, butyrophenone and reserpine),
Antihypertensives (reserpine, alpha-methyldopa and
spironolactone), Cardiac (digitalis), Gastrointestinal
(cimetidine, metoclopramide and domperidone),
Antituburculous (isoniazid), Cytoxic (cyclophospha-mide,
mustine, vincristine and mitotane) and Hormonal (sex
steroids, gonadotropins and antiandrogens). Use of these
drugs, however, will rarely cause gynecomastia. In some
instances, the feminization is due to effects of drugs on
liver functions.
 
Signs and Symptoms
 
There are very few signs and symptoms that are associated
with this disease. Signs may appear at any time in a male's
life, although the most common time of onset is during
puberty. At the first indication of the disease the patient
will feel pain and tender-ness in the breast area due to
the rapid development of the breast. The breasts grow
because of the enlargement of the glandular tissue. "The
concentric arrangement of the connective tissue around the
ducts is a characteristic feature of the active phase of
gynecomastia."(Delany, 67) The enlargement of the breast is
usually bilateral but some cases have unilateral
enlargement. In the case of unilateral enlargement,
"Induration, fixation, or bloody discharge should raise the
possibility of carcinoma."(Wyngaarden, 1450) Carcinoma is a
cancerous growth of the epithelial tissues. 

It may be hard to distinguish true breast tissue from
masses of adipose tissue without true enlargement
(lipomastia). In such cases, a real case of gynecomastia
can be distinguished by mammography or by sonography.
 
Early gynocomastia is characterized by "proliferation of
both the fibrobalstic stroma and the duct system, which
elongates, buds, and duplicates. As the disease progresses,
fibrosis and hyalinization are associated with the
regression of epithelial proliferation." Eventually the
number of ducts decreases, resolution occurs by reduction
in size of epithelial content leaving temporary hyaline
bands behind. (Isselbacher, 2037)
 
Diagnosis
 
A satisfactory diagnosis can be made in only half or less
of patients referred for gynecomastia. This is a result of
insufficient diagnostic techniques, causes that are still
undefined and/or difficult to diagnose, or in some
instances, gynecomastia may be normal rather than due to a
pathologic state. This disease should only be worked up
only if there is a negative drug history, if the breast is
tender (indicating rapid growth), or if the breast mass is
larger than 4 cm in diameter. A decision to perform an
endocrine evaluation depends on the clinical context. An
example would be gynecomastia associated with signs of
under androgenization.
 
Obesity can often be confused with gynecomastia. To prevent
this, the doctor can palpate the breast to see if there is
a lack of glandular elements that would indicate only
obesity.
 
Once the signs become evident, the doctor needs to assess
the patient with a number of test to give a proper
diagnosis since many other diseases and disorders are
commonly involved. This can be done with a physical
examination. The head and neck area may show signs of a
pituitary tumor or goiter which is found in Graves disease.
The skin and abdomen may reveal signs of liver failure and
the testes should be examined for asymmetric enlargement in
Klinefelter's syndrome. The doctor may consider liver
function tests of a karyotype if Kleinfelter's is
suspected. Other diseases related to gynecomastia include:
testicular tumors, hypo and hyperthyroidism, Cushing's
disease, cirrhosis, spinal cord lesions, Hodgkin's disease,
enzymatic defects in androgen synthesis and androgen
resistance syndromes, and many others.
 
The evaluation of patients with gynecomastia should include
a careful drug history, measurement and examination of the
testes, evaluation of liver function and endocrine
evaluation to include measurement of serum androstenedione
or 24-h urinary 17-keto-steriods, plasma estradiol and hCG,
and plasma luteinizing hormone (LH) and testosterone. If LH
is high and testosterone is low, the diagnosis is usually
testicular failure. If LH and testosterone are both low,
the diagnosis is usually increased estrogen production. If
they are both high, the diagnosis is either an
androgen-resistance state or a gonadotropin -secreting
tumor. In true gynecomastia these tests would prove to be
unnecessary because the symptoms would regress.
 
Treatment
 
When the primary cause can be identified and corrected,
breast enlargement usually diminishes until it usually
disappears. For example, "androgen replacement therapy may
produce dramatic improvement in men with testicular
insufficiency. However, if the gynecomastia is of long
duration (and fibrosis has replaced the original ductal
hyperplasia), correction of the primary defect may not be
followed by resolution." (Isselbacher, 2038) In this case,
surgery would be the only effective treatment. Candidates
for surgery include those with several psychologic and/or
cosmetic problems, continued growth, or a suspected
malignancy. 

The treatment selected for this disease is related to how
the patient was affected by the disease. The treatment for
a person who contracted the disease through certain drug
use will be treated different from a person who is affected
from a related disease. If gynecomastia is contracted
through drug use, the patient will needs to discontinue the
medications that are associated with the disease. The only
exception is when there is a life threatening illness
involved, and there is no alternative medication available.
 
For those suffering from gynecomastia, the doctor may
prescribe antiestrogens such as clomiphene citrate or
tamoxiten to eliminate tenderness of the breast. "The
non-aromatizable androgen dihydrotesosterone also has been
reported to reduce gynecomastia by reducing testicular
secretion of estradiol, by decreasing peripheral conversion
of precursors to estradiol and by increasing circulating
levels of androgen."(Kohler, 295) In patient with painful
gynecomastia and who are not candidates for other therapy,
treat-ments with antiestrogens such as tamoxifen may be
used.
 
When other related diseases are the cause for the onset of
gynecomastia, treatment of these diseases will often cure
gynecomastia, too. The removal of a sex steroid produc-ing
tumor or treatment of thyroidtoxicosis are two examples.
Testosterone treatment of androgen deficiency will also
cause great improvement in this condition. "Prophylactic
radiation of the breasts prior to the institution of
diethylstilbestrol therapy is effective in preventing
gynecomastia and has a low complication rate in elderly
men."(Isselbacher, 2039)
 
In most cases of true gynecomastia, the signs and symptoms
should regress in about a year. However, in the case of
severe gynecomsatia where the breast has an increase of
fibrous tissue stroma the patient will require a surgical
reduction mammo-plasty. Once this has been done the tissue
is sent to a lab to be examined. The results should show
elongated circular ducts imbedded in cellular fibrous
tissue with a rubbery fatty quality. From these laboratory
tests it can be determined if there is any cribiform
epithelial hyperlasia or a case of carcinoma. Although the
relative risk of carcinoma of the breast is increased in
men with gynecomastia, it is rare nevertheless.
 
Statistical Data
 
Gynecomastia is found only in males, and the signs can
appear any time in a male's lifetime. It is the leading
breast disorder in males and it accounts for 60% of all
disorders of the male breast. About 85% of male breast
masses are due to gynecomastia. Forty percent of the cases
affect pubescent boys occurring most often between the ages
of 14 to 15.5. Approximately 40% of normal men and up to
70% of hospitalized men have palpable breast tissue. Active
gynecomastia in autopsy data is between 5 and 9%. "More
than 80% of their hospitalized patients with a body mass
index of 25 kg/m2 or greater had gynocamastia."(Williams,
373) About 70% of pubertal males required no treatment. "If
the threshold for judging that the breast is enlarged is
set at 2.0cm in diameter, the incidence is 32-36% in normal
aged men 17-58 years."(Williams, 340) A bloody discharge is
present in about 60% of patients, while a milky discharge
is present in about 1% of patients.
 
Recent Research
 
In the Wilford Hall USAF Medical Center a set of
experiments were done to see if there is a connection
between 3B-HSD deficiency and gynecomastia. The researchers
tested a male who had developed right side gynecomastia at
the age of twenty-four. When a series of tests were run, no
other underlying conditions were evident. He was found only
to have a deficiency of 3B-HSD. The patient also had
abnormally high ratios of estradiol, estrogen and
aldosterone and other serums. This showed the presence of
adrenal sex steroid production on the right side of his
body.
 
This is not to say that all males patients with a
deficiency of 3B-HSD will develop gynecomastia. Other
patients with the same deficiency showed no signs, and
still others with normal 3B-HSD levels have also been found
to have reduced breast tissue. Researchers, however, do
believe that the deficiency of 3B-HSD later in life is
quite possibly a frequently unrecognized cause of new-onset
gynecomastia.
 
There are so many causes and factors that lead to the
disease gynecomastia that it is very difficult for
researchers to try to agree upon one main factor. So many
of the cases differ from one another, and, perhaps, no one
cause will ever be agreed upon as the leading factor of the
disease. As long as there is no other underlying disease or
disorder, gynecomastia is not a life threatening disease.
Experimentation with hormone therapy is the main research
being tested at this time.