Gynecomastia

Benign Enlargement of the Male Breast

Stephen J. Winters, M.D.
Professor of Medicine
Chief, Division of Endocrinology, Metabolism &
Diabetes
University of Louisville

A 65 year old man was admitted to the Geriatric Psychiatry service

because of depression. Gynecomastia was found, and an Endocrine
consultation was requested. He had been a poor student, and did not
graduate from high school. Three marriages ended in divorce, with no
children. There was no history of alcohol or drug use. His only
medication was hydrochlorthiazide-triamterene for hypertension. He was
found to have soft, smooth skin, and small testes. How should his
gynecomastia be evaluated and treated?

Gynecomastia: Clinical Findings

Subareolar
Bilateral or unilateral
Tenderness suggests an active process
Histology: ductular, connective and
adipose tissue

Men presenting with symptomatic breast

enlargement at the Denver VAH and UC HSC
Chronic liver or kidney disease-14
Hyperthyroid-2

Drug-induced-18

Breast cancer-3

" normal endocrine" tests

44 underwent excision
Idiopathic -53

Bowers et al, Am J Surg 1998

Gynecomastia: Pathogenesis
Altered androgen/estrogen regulation of
gene expression in the breast
Excessive estrogens
Endogenous
Exogenous
Testosterone deficiency
Altered hormone transport in plasma
Decreased androgen receptor, or increased
estrogen receptor activation

Breast is a target tissue for

estrogens and androgens

Estrogen receptor-a in breast cancer

Androgen Receptor
by immunocytochemistry

GnRH

Hypothalamus

Estradiol

a-subunit, LH-b

Target tissues

FSH-b

- Activin

+
Pituitary

Follistatin
LH FSH

Testosterone
placenta

Inhibin-B

Testis

hCG
hCG
Leydig
cells

Seminiferous
Tubules

Aromatase
Adiopose stroma
Smooth muscle
Kidney
Liver
CNS

Aromatase

PGE2/cAMP
Glucocorticoids
cytokines

LH/hCG

Aromatase
Testis

Estrogen production in normal men

Siiteri and MacDonald, 1975

LH

Etiologies of Gynecomastia

Developmental
Tumors
Drugs
Systemic disorders
Congenital and acquired hypogonadism
Miscellaneous

Prevalence of Developmental
Gynecomastia
Newborn
Adolescence: 50-70% of boys develop
gynecomastia at puberty
Adult men: Up to 70% of hospitalized men
have gynecomastia

Pubertal Gynecomastia

For the majority of teenagers, gynecomastia is a benign condition that

resolves as puberty progresses, but for some it progresses, and is a social
embarrassment.

Characteristics of Boys with Idiopathic

Pubertal Gynecomastia
Age yrs
Bilateral/Unilateral

Gynecomastia

Controls

(n=20)

(n=20)

13.9 0.2

14.2 0.14

14/6
22.9 0.17

23 0.1

Total testosterone ng/dl

275 30

291 34

Free testosterone pg/ml

1.44 0.15

1.46 0.19

138 15

109 15

117 8

107 6

Estradiol pg/ml

18.5 3.3

12.1 2.4

Leptin ng/ml

5.58 0.81

2.39 0.29*

BMI kg/m2

DHEAS mg/dl
Androstenedione ng/dl

Dundar et al, J Ped Endocrinol Metab, 2005

Aromatase excess Syndrome

(mutations of P450 aromatase gene)

Binder et al, JCEM 2005

patient

normal

T ng/dl

216-319

>350

90-190

>60

E2

25-32

<50

E1

77-126

<60

LH

2.3-5.0

0.6-10.5

FSH

0.6-1.2

1.4-11.8

Estrogen signaling pathways

TF

Cell membrane
nucleus

Gynecomastia due to Tumors

Testicular
Leydig cell E2
Sertoli cell

Testicular pain & enlargement,

feminization

Germ cell

Testicular pain & enlargement,

feminization, weight loss,
adenopathy
Abdominal pain, weight loss,
Cushings syndrome or
aldosterone excess
weight loss, anemia, respiratory
symptoms, adenopathy

Adrenal

hCG--E2

E1,E2

Ectopic hCG hCG--E2

In Search of a Cancer
Rudnick & Odell. NEJM 284:405, 1971
A 20 yo college student noted bilateral breast enlargement with
tenderness. Three mo later he was seen by an endocrinologist. In
addition to gynecomastia, the left testis was slightly larger than the
right. 24h urinary estrogens were 80 mg (nl 4-25), Urinary LH/hCG
was markedly increased. Extensive radiographic studies (in the days
before C/T and MR) failed to identify a tumor, including venous
sampling for CG. The scrotum was explored and both testes were
biopsied. 6 mo later the mediastinum was explored, and an enlarged
thymus was removed in which no tumor was found. 11 mo after
gynecomastia was first noted, he developed back pain anorexia,
weight loss and dyspnea. He had numerous metastatic lesions
throughout both lung fields, and his hCG level had risen markedly.
He died a few days later with disseminated choriocarcinoma
including a 4 mm nodule in the left testis.

Steroid hormone levels in men with testicular

germ cell tumors

I. Seminoma

II. Embryonal Carcinoma

III. Teratoma
IV. Teratocarcnoma
V. Choriocarcinoma

Stepanas et al, Cancer, 1978

An hCG-secreting testicular tumor revealed

by male infertility
Before
surgery
Testosterone (ng/ml)

7.9

After
surgery
5.2

Estadiol (pg/ml)

70

23

15-45

LH (mIU/ml)

<0.5

5.7

1-8

FSH (mIU/ml)

<0.5

11

1-11

SHBG (ng/ml)

22.3

31

17-34

b-hCG (mIU/ml)

152

<0.5

<5

Lefebvre et al, Andrologia 1993

Normal
values
3.5-10

Drug-induced gynecomastia

Estrogens
Gonadotropins
Spironolactone
Bicalutamide
Androgens
Calcium channel blockers
Digitalis
Cimetidine
Ketoconazole
Phenytoin

Amiodarone
Clomiphene
Metronidazole
Dopamine antagonists
Phenothiazines
Metoclopramide
Domperidone

Psychotropic drugs
Tricyclics
Diazepam

Drugs of abuse

Effects of spironolactone 200 mg

daily for 10 days in normal men
Baseline

During treatment
mean

Testosterone
ng/ml
Estradiol pg/ml

6.54 0.65

8.47

48 7

61

LH mIU/ml

14.8 12.8

16.3

FSH mIU/ml

6.73 0.81

7.44

GnRH

Hypothalamus

Estradiol

a-subunit, LH-b

FSH-b

- Activin

+
Pituitary

Follistatin
LH FSH

Inhibin-B

Testis

Testosterone
hCG
Leydig
cells

Seminiferous
Tubules

Bicalutamide-induced
Gynecomastia
The nonsteroidal antiandrogen bicalutamide
(Casodex) is used to prolong disease-free
survival in early stage prostate cancer.
In one study of 51 patients receiving
bicalutamide 150 mg, 37 (72.5%)
experienced gynecomastia and 41 (80.4%)
experienced breast pain within the 12 months
following initiation of treatment.
Tyrrell et al, Int J Rad Onc Biol Phy, 2004

Hormone levels in normal men treated

with bicalutamide 150 qd for 1 mo
baseline

treatment

LH mIU/ml

6.2 7.4

11.1 10.8

80

FSH mIU/ml

15.7 29.7

14.0 25.9

Total testosterone
nmol/L
Free T pmol/L

16.1 4.75

21.7 6.3

35

48 30.4

76 26.2

58

SHBG

83 11

93 20

12

Estradiol pmol/L

76.6 6.1

108.7 26

41

Salzstein et al, Prost Cancer Prost Disease, 2005

Exogenous estrogens
Administration of therapeutic estrogens
prostate cancer

Occupational exposure
Factory workers producing estrogens
morticians creams

Estrogens in the food chain

Phytoestrogens-soy
Meat from estrogen treated animals

Cannabinoids

Systemic disorders causing

Gynecomastia

Refeeding; recovery from severe illness

Chronic renal failure
Alcoholic cirrhosis
Hyperthyroidism
Aging

Hypogonadism in men with

alcoholic cirrhosis

Small testes
Reduced fertility
Soft, smooth skin
Decreased body hair
Decreased libido
Impotence
Gynecomastia
Palmar erythema
Spider angiomata

Endocrine Abnormalities in Men

with Alcoholic Cirrhosis

Low testosterone
Increased estrogens
Elevated LH>FSH
Increased SHBG
Increased ACTH, androstenedione and
cortisol

Gynecomastia in Alcoholic Cirrhosis

-

GnRH

CRF

Stress

Hypothalamus

Pituitary

a-subunit, LH-b
FSH-b

POMC

LH FSH

SHBG

ACTH

Hepatotoxicity/cytokines

Testosterone

Estradiol

GYNECOMASTIA

Estrone

Testicular toxin
cortisol
Androstenedione

Hormone Levels in Hyperthyroid Men

Hyperthyroid Normal men
Testosterone (ng/ml)

9.3 3.3*

5.4 1.6

Estradiol (pg/ml)

62 25*

32 11

SHBG (nM)

102 37*

19.0 5.0

BioT (ng/ml)

1.7 0.8*

3.1 1.9

17-OHP (ng/ml)

2.4 0.9*

1.1 0.5

299

92

164.5

72.2

LH (mIU/ml)
FSH (mIU/ml)
Abalovich et al,Thyroid, 1999

Causes of Male Hypogonadism

LH/FSH

Testosterone

Primary Testicular Elevated

Failure

Decreased
(occ. normal)

Hypogonadotropic Low or
normal
Hypogonadism

Decreased

Causes of Testicular Failure

Congenital
Klinefelter syndrome &
variants
Y chromosome mutations
Cryptorchidism
Congenital anorchia
Noonans syndrome
Lawrence-Moon-BardetBiedel syndrome
Myotonic muscular
dystrophy
Sickle Cell disease

Acquired

Trauma
Orchitis: mumps, leprosy
Spinal Cord Injury
Immune polyglandular
failure
Retroperitoneal Fibrosis
Cancer Chemotherapy
Testicular Irradiation

Clinical Features in Men with

Klinefelter Syndrome
Infertility
Small testes

99-100%
99-100%

Elevated gonadotropin
levels
Decreased testosterone
level
Decreased facial hair
Gynecomastia
Decreased pubic hair

90-100%

Small penis

10-25%

47,XXY

80-90%

Smyth & Bremner, Arch Int Med, 1998

65-85%
60-80%
50-75%
30-60%

Hormone concentrations in men with

Klinefelter syndrome
Klinefelter syndrome
(18-51yrs)
FSH (IU/L)

29.4 (12.1-61.2)

Normal men
(21-50 yrs)
2.7 (0.51-5.2)*

LH (IU/L)

7.8 (4.25-12.7)

1.8 (0.62-2.81)*

Testosterone (ng/dl) 316 (81-849)

680 (346-1075)*

Estradiol (pg/ml)

34 (3-65)

16 (UD-34)*

Inhibin-B (pg/ml)

113

18728*

from Wang et al, Clin Endo, 1975, and Anawalt et al. JCEM, 1996

Occupational and Social Status in Young

Men with Klinefelter Syndrome
Testosterone
treated

Untreated

Skilled
laborer

5 (36%)

1 (6%)

Unskilled

5 (36%)

10 (62%)

Student

2 (14%)

3 (19%)

Disabled

2 (14%)

2 (13%)

Nielsen et al, Clin Genet, 1988

Testoster- Untreated
one
treated

Well
adjusted

12 (86%)

9 (56%)

Unsatisf
actory

2 (14%)

7 (44%)

Causes of Hypogonadotropic Hypogonadism

Congenital
Acquired

Isolated HH

Panhypopituitarism

Pituitary adenoma

Granulomatous Autoimmune
diseases
hypophysitis

Prolactinoma

Histiocytosis

Hemochromatosis

Cushings Syndrome Acute and

chronic illness
Suprasellar tumors
Weight loss

Estrogenproducing tumors
X-irradiation

Craniopharyngioma

Malnutrition

Polyarteritis

Germinoma

Head trauma

Idiopathic

Gynecomastia in Disorders of
Sexual Differentation
Androgen receptor mutations
Complete testicular feminization
Partial androgen insensitivity syndromes

Expansion of CAG repeats in the AR gene

in Kennedy disease
Mutations in testosterone steroidogenesis
enzymes
True hermaphroditism
Mixed gonadal dysgenesis

Androgen levels in Obese Men

Nonobese
Obese
BMI< 35

Testosterone Free T
(nmol/L)
(nmol/L)

SHBG
Insulin
(nmol/L) (IU/L)

21.46.7

0.410.16

5017

9.93.3

16.54.7*

0.400.15

4014*

179*

0.290.11* 3614*

229*

BMI > 40 13.14.2*

Giagulli et al, JCEM, 1994

* vs nonobese,

E2

E1

Strain et al, Horm Metab Res, 2003

Kley et al, Metabolism, 1980

Strain et al, Horm Metab Res, 2003

Differentiation of Gynecomastia from Pseudo-gynecomastia

and Other Disorders by Physical Examination

Braunstein, NEJM 2007

Braunstein G. N Engl J Med 2007;357:1229-1237

Mammography in Male Patients With

Breast Symptoms (Hines et al, Mayo Clinic Proc, 2007)
Respective review of 212 mammograms
performed on 198 adult men

132 (62%) gynecomastia

20 (19%) normal
31 (15%) c/w other benign conditions
9 (4%) suspicious for cancer, 8 underwent biopsy
3 (1.5%) + Breast cancer; axillary nodes (1), nipple
retraction (1), skin retraction (1).

Gynecomastia can be evaluated and diagnosed

on the basis of clinical findings, and
mammography is unnecessary

Imaging characteristics of malignant lesions

of the male breast

Normal

Invasive ductal carcinoma

Chen, L. et al. Radiographics 2006; 26:993-1006

Management of Gynecomastia
Asymptomatic men with long standing
gynecomastia may need no treatment
Remove inciting agent or treat underlying
disease when possible
Tamixofen, raloxifene or anastrazole during
active proliferative phase (not FDA approved)
Radiation
Subcutaneous mastectomy/liposuction for
established disease since medically therapy is
generally ineffective

Breast events in 60 men with prostate

cancer treated with bicalutamide tamoxifen

Bicalutamide
months

Gynecomastia

29

43

49

Breast Pain

52

57

58

Either

54

58

59

Fradet et al, Eur Urol, 2007

Prophylactic breast irradiation with a single

dose of EBT for bicalutamide-induced
gynecomastia- 12 mo FU
RT +
bicalutamide

Sham RT +
bicalutamide

No gynecomastia

46.2%

9.3%

<2 cm

7.7%

3.7%

2-5 cm

32.7%

31.5%

>5 cm

11.5%

50%

Tyrrell et al, Int J Rad Onc Biol Phy, 2004

Percentage of boys with idiopathic pubertal gynecomastia

with 50% or greater reduction in total breast volume after 6
mo of treatment with anastrazole or placebo

Plourde, P. V. et al. J Clin Endocrinol Metab 2004;89:4428.

With established gynecomastia, plastic surgery remains the

mainstay of treatment when needed.

Summary
Gynecomastia is a common physical
finding. Sometimes it is a sign of
significant underlying disease. A detailed
clinical evaluation, and a few laboratory
tests generally identify the cause, and are
sufficient to guide treatment

Hormone levels at baseline and after 6 mo

of anastrazole treatment in 80 boys age 1118 with gynecomastia
Anastrasole

Placebo

Baseline

6 mo

Baseline

6 mo

Estradiol pg/ml

14.5

10

15

15

Testosterone ng/dl

205

343

248

259

LH mIU/ml

1.9

2.3

1.3

2.1

FSH mIU/ml

2.6

3.9

3.4

3.3

Plourde et al, J Clin Endocrinol Metat 2004

Risk factors for carcinoma of the

male breast

Family history of breast cancer

Increased BMI
Diabetes
Digoxin/Alpha methyldopa
Gynecomastia

Ewerts et al, Acta Oncologica 2001

Free testosterone levels in men with

prostate cancer treated with bicalutamide

+ tamoxifen
+ radiation