1|Gynecomastia
GYNECOMASTIA
SUBMITTED BY:
KHATRI, KAILASH,
N E PA L
MANDAL, OM PRAKASH,
RAVI, VIJAY,
N E PA L
INDIA
SAMA, HUMAIRA,
INDIA
GROUP: 4
SECTION: B
SCHEDULE: FRI-SAT 7-10 A.M, AVR-3
SUBMITTED TO: MR. LOUIE B. TADLAS, RMT
CLINICAL CHEMISTRY-2
Southwestern University, Cebu City, Cebu, Philippines
07-01-2016
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GYNECOMASTIA
Gynecomastia, the benign growth of glandular breast tissue in
men, is a common finding among males of varied ages.
Gynecomastia, which is associated with an increase in the
estrogen/androgen ratio, is commonly associated with three distinct
periods of life. First, transient gynecomastia can be found in 60 to
90% of all newborns because of high estrogen concentrations that
cross the placenta. The second peak occurs during puberty in 50 to
70% of normal boys. It is usually self-limited and may be due to low
serum testosterone, low DHT, or a high estrogen/androgen ratio.
The last peak is found in the adult population, most frequently
among men aged 50 to 80 years. Gynecomastia may be due to
testicular failure, resulting in an increased estrogen/ androgen ratio,
or to increased body fat, resulting in increased peripheral aromatization of testosterone to estradiol.
Gynecomastia may also develop as the result of iatrogenic causes, hyperthyroidism, or liver disease.
Liver disease impairs estrogen clearance and SHBG production, leading to increased bioavailable
estrogen and subsequent gynecomastia. Finally, germinal cell or nonendocrine tumors that produce
human chorionic gonadotropin (hCG), as well as estrogen-producing tumors of the adrenal glands, the
testes, or the liver, will cause gynecomastia. hCG stimulates testicular aromatase activity and estrogen
production, resulting in gynecomastia. In cases of striking gynecomastia in which history and physical
examination point to no specific disorder, measurements of hCG, plasma estradiol, testosterone, and
LH concentrations are appropriate.39 It is important to note that prolactin plays an important role in
galactorrhea (milk production), but only an indirect role in gynecomastia.
CLASSIFICATIONS
GM shows a gradation of clinical types that range from simple areolar protrusion to breasts with a
female appearance. The main clinical features characterizing GM are breast swelling, increased areolar
diameter, presence of an anomalous inframammary fold, glandular ptosis and skin redundancy.Based
upon this classification, in a standing position we classify astypes of GM into four grades of increasing
severity from I to IV, as follows
RISK FACTORS
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PUBERTAL GM
Mild
degrees
of
generally appear at
age, last for 6-12
spontaneously
the
cases.
The
enlargement may be
tender.
The
reach
severe
to
an
effeminate
Such
occurrences
perceptions,
sexual sphere.
AGING GM
Causes
Physiological
factors
Puberty or aging
Endocrine
tumors
Testicular, adrenocortical or
pituitary tumors, or ectopic hCGsecretion
Endocrine
dysfunctions
Hypogonadism, hyperthyroidism,
obesity or refeeding
Nonendocrine
diseases
Cirrhosis, renal failure or HIV
pubertal
GM
13 or 14 years of
months and then
regress in 95% of
glandular
asymmetric
and
hypertrophy
may
proportions, leading
appearance in boys.
may
alter
selfespecially in the
Older men over the
age of 65 years
often present relative
hypogonadism with
Drug-induced Medications, anabolic steroids or
a decline in plasma
testosterone levels,
factors
illicit drugs
elevation of SHBG
and decrease in free
Idiopathic factors
testosterone.
Furthermore, there
is progressive adiposity favoring peripheral aromatase activity. Several comorbidities may be common
at this age, and any medication used may contribute towards provoking or aggravating GM.
ENDOCRINE TUMORS
Benign testicular tumors (Sertoli or Leydig cell tumors) may secrete estradiol. Secondary
suppression of LH levels interferes negatively with testosterone synthesis. The elevated estrogen
levels raise the serum concentration of SHBG, which preferentially binds testosterone, thereby
lowering the free testosterone levels. Choriocarcinoma and other germ cell tumors produce hCG and
stimulate testicular cells (Leydig) to secrete estradiol, and furthermore, often cause GM. These tumors
may be palpable or be detected only by means of ultrasound. Other hCG secreting tumors of ectopic
origin may lead to GM (e.g. carcinomas of the lungs, liver, stomach and kidneys).
Pituitary adenomas producing prolactin (prolactinomas) may also induce GM.
Adrenocortical tumors are generally large malignant types of neoplasia, with predominant incidence in
young and middle-aged men. They are feminizing tumors with direct secretion of estrogens and steroid
precursors, like androstenedione. The serum estrogen elevation also suppresses LH-mediated
testosterone production.
ENDOCRINE DYSFUNCTIONS
Severe hyperthyroidism increases serum SHBG. Since estradiol binds less avidly to SHBG than does
testosterone, there appears to be an increase in the ratio of free estradiol to free testosterone, thus
resulting in clinically evident GM in 10 to 40% of the patients. Primary gonadal failure as a result of
testicular trauma, chemotherapy, mumps, orchitis and leprosy can cause GM by lowering the serum
testosterone levels, inducing elevation of LH and stimulating the remaining Leydig cells to secrete
estrogens. Klinefelter syndrome is a chromosomal disorder (47 XXY karyotype) associated with
hypogonadism and infertility; in these men, GM is seen in almost 70%. The reason why the presence of
an extra X chromosome is linked to GM is unclear. Male pseudo hermaphroditism with Morris syndrome
(testicular feminization) is often associated with normal female breast appearance due to gonadal
estrogen production. Low testosterone and elevated LH levels indicate primary hypogonadism.
Findings of low testosterone levels with normal LH assays denote secondary testicular failure.
It is noteworthy that men with long-standing type 1 diabetes may develop diabetic mastopathy,
presenting hard diffuse enlargements of one or both breasts. An inflammatory lesion characterized by
lymphocytic infiltration of the mammary ducts and lobules is found microscopically.
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Other endocrine-metabolic conditions related to the development of GM include metabolic syndrome,
refeeding after severe starvation and substantial weight loss and functional hyperprolactinemia.
NON-ENDOCRINE DISEASES
The chief sex hormone abnormalities in cases of liver cirrhosis are decreased serum testosterone levels
and increased estradiol levels. The mechanisms that cause liver cirrhosis to lead to GM in a small
percentage of cases have yet to be elucidated. The causes are probably multifactorial. Men with
chronic renal failure are often hypo gonadal, with defects in testicular steroidogenesis. Many of these
men develop GM.
In men with HIV, GM occurs in 2-3%.GM can be triggered either by lipodystrophy or by highly active
antiretroviral therapy.
DRUG INDUCTION
Drug-induced GM merits deep consideration as it may account for as many as 25% of all cases of newonset GM in adults. Even though the mechanisms through which a long list of drugs can cause GM are
not fully clear, they are derived from estrogen-like activities, stimulation of testicular production of
estrogens, inhibition of testosterone synthesis or blockade of androgen action.
IDIOPATHIC GM
So far, at least 20 clinical conditions and 30 medications have been implicated in relation to causing
GM. However, the etiology of GM is still only understood to a limited extent, and up to 50% of the
cases may have no obvious cause.33 Given the high frequency of idiopathic GM, we hypothesize that
multiple environmental endocrine disruptors are likely to be involved in excessive breast development
in men.
PATHOPHYSIOLOGY
In boys, the main sex hormone is testosterone, which is secreted by the
testes. In girls, the main sex hormone is estrogen, which is secreted by the
ovaries. However, both hormones are secreted in both sexes. Some production
of estrogen occurs in the testes, and some production of testosterone occurs
in the ovaries. Gynecomastia has long been considered the result of an
imbalance between estrogens, which stimulate breast tissue, and androgens,
which antagonize this effect. An alteration in the normal ratio of estrogen to
androgen has been found in patients with gynecomastia in association with
many different etiological factors. Estradiol is the growth hormone of the
breast in women, and an excess of estradiol leads to the proliferation of breast
tissue. Under normal circumstances, most estradiol in men is derived from the
peripheral conversion of testosterone and adrenal estrogen. The basic
mechanisms of physiologic gynecomastia have been postulated to represent a
decrease in androgen production, an absolute increase in estrogen production,
and an increased availability of estrogen precursors for peripheral conversion to estradiol. See the
image below.
The etiology of most cases of gynecomastia remains unknown. The number of breast malignancies
does not appear to be increased in patients with idiopathic gynecomastia. Patients who present with
gynecomastia and have Klinefelter syndrome do exhibit an increased incidence of breast malignancies.
Pensler et al noted that patients with Klinefelter syndrome exhibited elevated estrogen and
progesterone receptors in their breast tissue. The presence of elevated estrogen and progesterone
receptors in patients with Klinefelter syndrome provides a potential mechanism by which these
patients may develop breast neoplasms. By contrast, patients with idiopathic gynecomastia did not
demonstrate an increased number of estrogen or progesterone receptors. Also, the binding affinity of
the receptors in both groups were not affected. The absence of elevated progesterone or estrogen
receptors in patients with idiopathic gynecomastia helps to explain why these patients rarely manifest
breast malignancy.
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HALLMARK OF DISEASE
In gynecomastia, there is enlargement of the male breast due to benign ductal and stromal
proliferation. A hallmark of gynecomastia is its central symmetric location under the nipple.
CASE PRESENTATION
20 yo Latino male in general good health with 2yrs of unilateral tender, enlarged left breast. Noticed
enlarged left breast with increasing tenderness and size 2yrs ago. Dull pain to touch and with
movement. Denies nipple discharge/galactorrhea. Denies history of trauma. Denies current and prior
use of Alcohol, Tobacco, and Drugs. Cannot remember when physical changes of puberty began. The
physical exams showed following:
BP116/59
Gen: Thin, flat affect, NAD, well dressed, answering questions appropriately, emotionally labile
during interview
Breasts: Visually enlarged left breast. Enlarged breast tissue 4cm with rubbery amorphous
mass above nipple, no discrete masses. +TTP. No skin discolorations, dimpling, nipple
retraction or discharge.
GU: Normal male genitalia. Bilateral descended testes, non-tender, no masses palpated
Neuro: A&O x 4, CN II-XII intact, good strength
Referral to breast clinic: Scheduled mammogram and advised to return if increase in breast
size, pain, or discrete mass.
DIAGNOSIS
The definition of gynecomastia is the presence of breast tissue greater than 0.5 cm in diameter in a
male. As previously discussed, gynecomastia is the presence of true breast (glandular) tissue,
generally located around the nipple. Fat deposition is not considered to be true gynecomastia.
In most cases, gynecomastia can be diagnosed by a physical examination. A careful medical history is
also important, including medication and drug use. If there is a suspicion of cancer, a mammogram
may be ordered by a health care practitioner. Further tests may be recommended to help establish the
cause of gynecomastia in certain cases. These can include blood tests to examine liver, kidney, and
thyroid function. Measurement of hormone levels in the bloodstream may also be recommended in
some cases.
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Initial tests to determine the cause of gynecomastia
may include:
Blood tests
Mammograms
May need further testing depending on initial test
results, including:
Computerized tomography (CT) scans
Magnetic resonance imaging (MRI) scans
Testicular ultrasounds
Tissue biopsies
LABAROTARY EVALUATION
Routine biochemical testing should evaluate thyroid,
liver, and kidney function, along with measurements
of serum testosterone (total and/or bioavailable), estradiol, LH, FSH, prolactin, and hCG
EPIDEMIOLOGY
Gynecomastia has three peaks.
Infancy: 60-90% transient due to high maternal estrogen. Normally regresses over 2-3 week
period.
2. Adolescence: 4-69% with wide variation due to examiner observation. Onset 10-12y/o and
peaks 13-14y/o. normally regresses w/in 18mo and persistence uncommon after 17y/o.
3. Older men: 24-65% with highest prevalence in the 50-80y/o.
MANAGEMENT & TREATMENT
Gynecomastia, especially in pubertal males, often goes away on its own within about six months, so
observation is preferred over specific treatment in many cases. Stopping any offending medications
and treatment of underlying medical conditions that cause gynecomastia are also mainstays of
treatment.
Treatments are also available to specifically address the problem of gynecomastia, but data on their
effectiveness are limited, and no drugs have yet been approved by the U.S. Food and Drug
Administration (FDA) for treatment of gynecomastia. Medications are more effective in reducing
gynecomastia in the early stages, since scarring often occurs after about 12 months. After the tissue
has become scarred, medications are not likely to be effective, and surgical removal is the only
possible treatment.
Medications that have been used to treat gynecomastia include:
Testosterone replacement has been effective in older men with low levels of testosterone, but
it is not effective for men who have normal levels of the male hormone.
Clomiphene gynecomastia. It can be taken for up to 6 months.
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The selective estrogen receptor modulator (SERM) tamoxifen (Nolvadex) has been shown to
reduce breast volume in gynecomastia, it was not able to entirely eliminate all the breast
tissue. This type of therapy is most often used for severe or painful gynecomastia.
Danazol is a synthetic derivative of testosterone that decreases estrogen synthesis by the
testes. It works by inhibition of pituitary secretion of LH and follicle-stimulating hormone (FSH),
substances that direct the sex organs to produce hormones. It is less commonly used to treat
gynecomastia than other medications.
CONCLUSION
GM is a common condition that may be attributable to an estrogen/androgen imbalance caused by
several etiological factors. After confirming the diagnosis, searching for a specific cause and classifying
the case according to severity grade, the therapy for GM should be personalized. Lifestyle guidance,
reassurance, medical treatment and surgical correction are valid tailored therapeutic options.
