gynecomastia. question 24 year-old male presents to pcp for painless enlargement of breasts for past...

GynecomastiaGynecomastia

QuestionQuestion

24 year-old male presents to PCP for painless 24 year-old male presents to PCP for painless enlargement of breasts for past six monthsenlargement of breasts for past six months Gradual onset without discharge or painGradual onset without discharge or pain

No past medical history, medications, or No past medical history, medications, or supplementssupplements Social ETOH use – less than 5 drinks per weekSocial ETOH use – less than 5 drinks per week

Exam:Exam: BMI: 31BMI: 31 Breast – bilateral retro-areolar rubbery massBreast – bilateral retro-areolar rubbery mass Testicular – No masses, tenderness; normal sizeTesticular – No masses, tenderness; normal size

Evaluation:Evaluation: LH – LH – 4.8 mIU/ml 4.8 mIU/ml (NML 1.5-9.3 mIU/ml)(NML 1.5-9.3 mIU/ml) Testosterone – Testosterone – 482 ng/dl 482 ng/dl (NML 241/827 (NML 241/827

ng/dl)ng/dl) TSH - TSH - 0.52 mIU/ml0.52 mIU/ml (NML 0.4-5.5 mIU/ml)(NML 0.4-5.5 mIU/ml)

What is the next step?What is the next step?

A)A) Observation – this will likely regressObservation – this will likely regressB)B) Referral for elective surgery – patient Referral for elective surgery – patient

has cosmetic concerns regarding has cosmetic concerns regarding breastsbreasts

C)C) Trial of tamoxifen for six monthsTrial of tamoxifen for six monthsD)D) Encourage weight loss and ETOH Encourage weight loss and ETOH

avoidance with follow-upavoidance with follow-upE)E) Work-up is not complete – continue Work-up is not complete – continue

evaluationevaluation

Take Home PointsTake Home Points

Gynecomastia may be a transient complaint, Gynecomastia may be a transient complaint, or the only manifestation of a fatal diseaseor the only manifestation of a fatal disease

Gynecomastia requires a thorough Gynecomastia requires a thorough investigation for cause; including investigation for cause; including hormonal evaluation if indicatedhormonal evaluation if indicated

Treatment of gynecomastia is cause specificTreatment of gynecomastia is cause specific

DefinitionDefinition

Clinical:Clinical: Rubbery or firm mass extending Rubbery or firm mass extending

concentrically from the nippleconcentrically from the nipple Pathologic:Pathologic:

Benign proliferation of the glandular Benign proliferation of the glandular tissue of the male breasttissue of the male breast

Pseudo-gynecomastia Pseudo-gynecomastia Fat deposition without glandular Fat deposition without glandular

proliferationproliferation

HistologyHistology

Initial:Initial:1) Ductal epithelial 1) Ductal epithelial

hyperplasiahyperplasia2) Proliferation of 2) Proliferation of

periductal inflammatory periductal inflammatory cellscells

3) Periductal fibroblastic 3) Periductal fibroblastic proliferation. proliferation.

Late (after >12 month):Late (after >12 month):1) Increased number of 1) Increased number of

ducts with dilatationducts with dilatation2) No epithelial cell 2) No epithelial cell

proliferationproliferation3) Increased fibrosis3) Increased fibrosis

Normal male breast

Early gynecomastiaEarly gynecomastia

www.uptodate.com

EpidemiologyEpidemiology

Common at birth Common at birth Found in up to 60 - 90% of male infantsFound in up to 60 - 90% of male infants

Second peak in pubertySecond peak in puberty Estimated at 4-69% of malesEstimated at 4-69% of males Most common ages 11-12 (Tanner 3)Most common ages 11-12 (Tanner 3) Uncommon after age 17Uncommon after age 17

Highest peak ages > 50Highest peak ages > 50 Estimated 24-65% of men affectedEstimated 24-65% of men affected

Braunstein G. N Engl J Med 1993;328:490-495

Braunstein. Gynecomastia. In: Diseases of the Breast. Harris, Lippincott-Raven, Philadelphia 1996. p. 54.

Prevalence of gynecomastia from multiple population studies

Steroid PathwaysSteroid Pathways

PathophysiologyPathophysiology


EtiologiesEtiologies

Persistent pubertal gynecomastia Persistent pubertal gynecomastia 25%25% Medications Medications 10 - 25% 10 - 25% Idiopathic Idiopathic 25% 25% Cirrhosis or malnutrition Cirrhosis or malnutrition 8% 8% Hypogonadism:Hypogonadism:

HypergonadotropicHypergonadotropic 8 %8 % Hypogonadotropic Hypogonadotropic 2 % 2 %

Testicular tumors Testicular tumors 3% 3% Hyperthyroidism Hyperthyroidism 1.5% 1.5% Chronic renal insufficiency Chronic renal insufficiency 1% 1%

Braunstein, Glenn.Braunstein, Glenn. “Gynecomastia”. NEJM 1993;328:490-95“Gynecomastia”. NEJM 1993;328:490-95

Persistent Pubertal Persistent Pubertal GynecomastiaGynecomastia

Usually occurs age Usually occurs age 11-12 (Tanner 3)11-12 (Tanner 3) Initial estradiol Initial estradiol

surge at pubertysurge at puberty Followed by Followed by

testosterone surgetestosterone surge Persists up to two Persists up to two

years in 25%years in 25% Hands, L. Hands, L. GynaecomastiaGynaecomastia. Br. J. Surg. 1991, 78:907-. Br. J. Surg. 1991, 78:907-911911


Persistent pubertal gynecomastia Persistent pubertal gynecomastia 25% 25% Medications Medications 10 - 25% 10 - 25% Idiopathic Idiopathic 25% 25% Cirrhosis or malnutrition Cirrhosis or malnutrition 8% 8% Hypogonadism:Hypogonadism:




MedicationsMedications


Spironolactone

Symptoms in almost every male at doses Symptoms in almost every male at doses of 100 mg/dayof 100 mg/day

Small study of six patients on Small study of six patients on spironolactone with gynecomastia spironolactone with gynecomastia compared to control patientscompared to control patients Spironolactone patients had significantly lower Spironolactone patients had significantly lower

testosterone and higher estradiol (p<0.01)testosterone and higher estradiol (p<0.01) Androgen receptor antagonistAndrogen receptor antagonist Increased peripheral aromatization to estradiolIncreased peripheral aromatization to estradiol Decreased testosterone production Decreased testosterone production

Rose, L. Ann Intern Med 1977;87:398-403Rose, L. Ann Intern Med 1977;87:398-403

Spironolactone

Randomized Aldactone Evaluation Study (RALES) Evaluate spironolactone in heart failure

Double-blind, placebo controlled with 1663 patients included in study

Spironolactone or placebo at 25 – 50 mg daily Trial stopped early due to significant reduction in

cardiovascular mortality Gynecomastia

Treatment group - 9% (p<0.001) Placebo group - 1%

In a second study, epleronone, a selective aldosterone antagonist, had equal incidence of gynecomastia as placebo in over 6500 patients

Pitt, B et. Al. NEJM 1999;341:709-17; NEJM 2003;348:1309-21Pitt, B et. Al. NEJM 1999;341:709-17; NEJM 2003;348:1309-21

Anti-Ulcer MedicationsAnti-Ulcer Medications

Many case reports of gynecomastia Many case reports of gynecomastia related to anti-histamine and proton pump related to anti-histamine and proton pump inhibitor medicationsinhibitor medications

Open cohort study from UK – 1989-92Open cohort study from UK – 1989-92 Evaluated 81,535 men aged 25-84 given Evaluated 81,535 men aged 25-84 given

prescription for cimetidine, omeprazole, or prescription for cimetidine, omeprazole, or ranitidineranitidine

Omeprazole and ranitidine had no increased risk of Omeprazole and ranitidine had no increased risk of gynecomastiagynecomastia

Cimetidine had significant increased risk for Cimetidine had significant increased risk for gynecomastia (RR 7.2)gynecomastia (RR 7.2)

Noted verapamil RR 9.7 and spironolactone RR 9.3Noted verapamil RR 9.7 and spironolactone RR 9.3

Rodriquez, LA. “Risk of gynaecomastia associated with cimetidine, opeprazole, and other antiulcer drugs”. BMJ Rodriquez, LA. “Risk of gynaecomastia associated with cimetidine, opeprazole, and other antiulcer drugs”. BMJ 1994;308:503-61994;308:503-6

Anti-Androgen MedicationsAnti-Androgen Medications

Flutamide, bicalutamide, nilutamide bicalutamide, nilutamide Used commonly in prostate cancer to Used commonly in prostate cancer to

suppress androgen stimulation of cancersuppress androgen stimulation of cancer Bind to androgen receptors to block Bind to androgen receptors to block

testosterone and DHT responsetestosterone and DHT response Excess testosterone aromatized to estradiolExcess testosterone aromatized to estradiol

Finasteride Finasteride 5-alpha reductase inhibitor5-alpha reductase inhibitor

Blocks conversion of testosterone to DHTBlocks conversion of testosterone to DHT

DrugsDrugs

Other well described Other well described association:association: ETOHETOH

Inhibition of H-P-T axis as well as Inhibition of H-P-T axis as well as direct testicular toxicitydirect testicular toxicity

MarijuanaMarijuana Androgen receptor antagonistAndrogen receptor antagonist

Tree oils and lotionsTree oils and lotions Any estrogen containing creamsAny estrogen containing creams HAARTHAART

More commonly pseudo-More commonly pseudo-gynecomastiagynecomastia

Lipodystrophy also possibleLipodystrophy also possibleWarren, S. “Lipodystrophy” NEJM 2005;352:62


Persistent pubertal gynecomastia Persistent pubertal gynecomastia 25% 25% Medications Medications 10 - 25% 10 - 25% Idiopathic Idiopathic 25%25% Cirrhosis or malnutrition Cirrhosis or malnutrition 8% 8% Hypogonadism:Hypogonadism:




Idiopathic/Obesity/Normal Idiopathic/Obesity/Normal AgingAging

Androgen Androgen InsensitivityInsensitivity

Aromatase excessAromatase excess Due to excess Due to excess

adipose tissueadipose tissue Hereditary Hereditary

aromatase excessaromatase excess

Idiopathic/Obesity/Normal Idiopathic/Obesity/Normal AgingAging

Braunstein, Glenn.Braunstein, Glenn. “Aromatase and Gynecomastia”. Endocrine-Related Cancer 1999;6:315-24“Aromatase and Gynecomastia”. Endocrine-Related Cancer 1999;6:315-24

Cirrhosis/StarvationCirrhosis/Starvation

Several mechanisms:Several mechanisms: Decreased clearance of androgens Decreased clearance of androgens

leading to increased conversion to leading to increased conversion to estrogenestrogen

Increased sex hormone binding globulin Increased sex hormone binding globulin (SHBG) decreasing free testosterone(SHBG) decreasing free testosterone

Decreased testosterone productionDecreased testosterone production



HypergonadotropicHypergonadotropic 8 %8 % HypogonadotropicHypogonadotropic 2 % 2 %



Hypergonadotropic HypogonadismHypergonadotropic Hypogonadism

Predominance of adrenal Predominance of adrenal androgens with peripheral androgens with peripheral conversion to estradiol conversion to estradiol Congenital:Congenital:

Klinefelter’s SyndromeKlinefelter’s Syndrome CryptorchidismCryptorchidism Myotonic dystrophy and other rare Myotonic dystrophy and other rare

androgen receptor disordersandrogen receptor disorders Acquired:Acquired:

DrugsDrugs Viral or traumatic injuryViral or traumatic injury

HIV and mumpsHIV and mumps Radiation injuryRadiation injury Chronic illnessChronic illness

HemochromatosisHemochromatosis Autoimmune diseaseAutoimmune disease

Bagatell, C. Bagatell, C. Androgens in Men – Uses and Androgens in Men – Uses and AbusesAbuses. NEJM 1996;334:707-14. NEJM 1996;334:707-14

Hypogonadotropic Hypogonadotropic HypogonadismHypogonadism

Predominance Predominance of adrenal of adrenal androgensandrogens

Testicular Testicular estradiol estradiol production production may persistmay persist

Testicular NeoplasmTesticular Neoplasm

Germ cell cancers (95% of testicular cancer) are Germ cell cancers (95% of testicular cancer) are associated with gynecomastia in 2.5-6% associated with gynecomastia in 2.5-6% Most common with elevated hCG from choriocarcinomaMost common with elevated hCG from choriocarcinoma

hCG stimulates aromatase in Leydig cellshCG stimulates aromatase in Leydig cells Poor prognostic indicator – 50% mortality rate in small case Poor prognostic indicator – 50% mortality rate in small case

series of casesseries of cases Incidence of gynecomastia is 20-30% with Leydig Incidence of gynecomastia is 20-30% with Leydig

cell cancers (2% of all testicular cancers)cell cancers (2% of all testicular cancers) Leydig cells produce high levels of estradiolLeydig cells produce high levels of estradiol

Commonly occurs after treatment of testicular Commonly occurs after treatment of testicular cancer due to hypergonadotropic hypogonadismcancer due to hypergonadotropic hypogonadism

Does not change prognosis if symptoms occur after Does not change prognosis if symptoms occur after treatmenttreatment

Tseng, A. “Gynecomastia in testicular cancer patients. Prognostic and Tseng, A. “Gynecomastia in testicular cancer patients. Prognostic and therapeutic implications.” Cancer 1985; 56:2534. therapeutic implications.” Cancer 1985; 56:2534.

ThyrotoxicosisThyrotoxicosis

Multiple pathways:Multiple pathways: Increased Sex Increased Sex

Hormone Binding Hormone Binding Globulin (SHBG)Globulin (SHBG)

Increased Increased androstenedione androstenedione production rates production rates

Increased Increased peripheral aromatization of testosterone to estradiol

Pearlman, G. The Endocrinologist 2006;16:109-15


Persistent pubertal gynecomastia Persistent pubertal gynecomastia 25% 25% Medications Medications 10 - 25% 10 - 25% Idiopathic Idiopathic 25% 25% Cirrhosis or malnutritionCirrhosis or malnutrition 8% 8% Hypogonadism:Hypogonadism:




Renal FailureRenal Failure

Similar mechanism to starvationSimilar mechanism to starvation Decreased testicular function preceding Decreased testicular function preceding

dialysisdialysis Increased hormone production after Increased hormone production after

initiating dialysis with increased initiating dialysis with increased estrogens firstestrogens first

Review:Review:Etiologies of GynecomastiaEtiologies of Gynecomastia

Braunstein G. N Engl J Med 1993;328:490-495 www.cbsnews.com

Differential DiagnosisDifferential Diagnosis

Pseudo-Pseudo-gynecomastiagynecomastia

Breast cancerBreast cancer Lipoma or cystLipoma or cyst

Hannekin, S. Hannekin, S. Ann Int Med 2004;140:497-98

EvaluationEvaluation

History and Physical Exam Including:History and Physical Exam Including: Onset and duration of symptomsOnset and duration of symptoms Detailed medication historyDetailed medication history Evaluation for evidence of other systemic diseaseEvaluation for evidence of other systemic disease Physical exam focus:Physical exam focus:

Body habitus, body mass indexBody habitus, body mass index Bilateral breast examBilateral breast exam Testicular exam: Size, massesTesticular exam: Size, masses Hair distributionHair distribution Thyroid examThyroid exam

Braunstein, Glenn.Braunstein, Glenn. Gynecomastia. Gynecomastia. NEJM 2007;357:1229-35 NEJM 2007;357:1229-35

EvaluationEvaluation

Red flags:Red flags: New onsetNew onset No risk factors or common medicationsNo risk factors or common medications Young, post-puberty Young, post-puberty PainfulPainful Hard noduleHard nodule Nipple dischargeNipple discharge

Hormonal EvaluationHormonal Evaluation

Indicated if no obvious cause for Indicated if no obvious cause for symptoms on history and physicalsymptoms on history and physical

Laboratory evaluation:Laboratory evaluation: LHLH hCGhCG Testosterone (including free fraction)Testosterone (including free fraction) EstradiolEstradiol TSHTSH


Elevated hCG = cancerLow testosterone = hypogonadism

High estradiol = cancer or aromatase

Radiographic EvaluationRadiographic Evaluation

Consider testicular ultrasound Consider testicular ultrasound Mammogram to evaluate for cancer:Mammogram to evaluate for cancer:

Klinefelter’s SyndromeKlinefelter’s Syndrome Family history of male breast cancerFamily history of male breast cancer Suspicious massSuspicious mass

Ultrasound effective to diagnose Ultrasound effective to diagnose pseudo-gynecomastiapseudo-gynecomastia

Appelbaum, AH. Scientific Exhibit Appelbaum, AH. Scientific Exhibit 1999;19:599-681999;19:599-68

MammographyMammography

In experienced In experienced centers:centers: Gynecomastia can be Gynecomastia can be

diagnosed diagnosed Suspicious nodular Suspicious nodular

findings must be findings must be evaluated with evaluated with biopsybiopsy

Overlap between Overlap between malignant and malignant and benign limit utilitybenign limit utility

Appelbaum, AH. Scientific Exhibit Appelbaum, AH. Scientific Exhibit 1999;19:599-681999;19:599-68

TreatmentTreatment

TreatmentTreatment

Cause specific:Cause specific: Stop offending medicationsStop offending medications Weight lossWeight loss Alcohol cessationAlcohol cessation Treatment of underlying disorderTreatment of underlying disorder Most idiopathic cases will resolve or Most idiopathic cases will resolve or

regress within six monthsregress within six months

TreatmentTreatment

Medical therapyMedical therapy No FDA approved treatment currentlyNo FDA approved treatment currently

Testosterone therapy if indicated for Testosterone therapy if indicated for hypogonadismhypogonadism

Increased conversion to estradiol may Increased conversion to estradiol may worsen symptomsworsen symptoms

Anti-estrogen therapy: Tamoxifen or Anti-estrogen therapy: Tamoxifen or clomiphene clomiphene

Aromatase inhibitor therapy: Aromatase inhibitor therapy: anastrozole

Anti-estrogen TherapyAnti-estrogen Therapy

Tamoxifen in adolescentsTamoxifen in adolescents No double-blind placebo controlled studiesNo double-blind placebo controlled studies Retrospective review of 14 patients found reduction Retrospective review of 14 patients found reduction

in breast size, but 40% still went to surgeryin breast size, but 40% still went to surgery Tamoxifen in prostate cancerTamoxifen in prostate cancer

Somewhat effective in treating the gynecomastia Somewhat effective in treating the gynecomastia induced by anti-androgen treatmentinduced by anti-androgen treatment

Decreased breast tenderness and slight reduction in Decreased breast tenderness and slight reduction in size size

No adverse events or increase cancer risk on No adverse events or increase cancer risk on therapytherapy

Staiman VR. ”Tamoxifen for flutamide/finasteride-induced gynecomastia.” Staiman VR. ”Tamoxifen for flutamide/finasteride-induced gynecomastia.”

Urology 1997;50:929-933 Urology 1997;50:929-933 Lawrence, SE. “Beneficial effects of raloxifene and tamoxifen in the treatment of pubertal Lawrence, SE. “Beneficial effects of raloxifene and tamoxifen in the treatment of pubertal gynecomastia.” J Pediatr 2004; 145:71.gynecomastia.” J Pediatr 2004; 145:71.

Aromatase Inhibitor Aromatase Inhibitor

Double-blind, placebo controlled study Double-blind, placebo controlled study of 87 male patients aged 11-18 years-of 87 male patients aged 11-18 years-oldold Treated with anastrozole (Arimidex) 1mg Treated with anastrozole (Arimidex) 1mg

dailydaily Primary endpoint >50% reduction in breast Primary endpoint >50% reduction in breast

volumevolume No significant difference between groups No significant difference between groups

after 6 months of treatmentafter 6 months of treatment Primary endpoint met in 38% of treatment arm Primary endpoint met in 38% of treatment arm

and 31% of placebo arm (p=0.47)and 31% of placebo arm (p=0.47)

Plourde, P. J Clin Endocrinol Metab 2004;89:4428-33Plourde, P. J Clin Endocrinol Metab 2004;89:4428-33

Gynecomastia in Prostate Gynecomastia in Prostate CancerCancer

Double-blind, placebo controlled Double-blind, placebo controlled study of 114 patient treated with study of 114 patient treated with bicalutamide (Casodex) for advanced bicalutamide (Casodex) for advanced prostate cancerprostate cancer Prophylactic treatment with placebo, Prophylactic treatment with placebo,

tamoxifen, or anastrozoletamoxifen, or anastrozole Assessed with clinical exam, ultrasound, Assessed with clinical exam, ultrasound,

and calipersand calipers

Boccardo, F. J Clin Onc 2005;23:808-15

Gynecomastia in Prostate Gynecomastia in Prostate CancerCancer

Boccardo, F. J Clin Onc 2005;23:808-15

Tamoxifen group

RecommendationsRecommendations

AdolescentsAdolescents If negative work-up and persistent severe If negative work-up and persistent severe

symptoms, a brief three month trial of symptoms, a brief three month trial of tamoxifen 10 mg daily can be considered (tamoxifen 10 mg daily can be considered (3C3C) )

Adults (including prostate cancer patients)Adults (including prostate cancer patients) If negative work-up and persistent severe If negative work-up and persistent severe

symptoms, a three to six month trial of symptoms, a three to six month trial of tamoxifen may be considered (tamoxifen may be considered (3C3C))

Aromatase inhibitors are not recommended Aromatase inhibitors are not recommended ((2B2B))

If persistently troublesome for >1 year, If persistently troublesome for >1 year, surgical intervention may be considered (surgical intervention may be considered (2B2B))

Braunstein, Glenn. Uptodate.com

SurgerySurgery Consider surgical options:Consider surgical options:

After 12 months of symptomsAfter 12 months of symptoms For pain or emotional distressFor pain or emotional distress When unable to correct underlying conditionWhen unable to correct underlying condition

Low complication risk when performed at Low complication risk when performed at experienced centerexperienced center

Take Home PointsTake Home Points

Gynecomastia may be a transient Gynecomastia may be a transient complaint, or the only manifestation of a complaint, or the only manifestation of a fatal diseasefatal disease

Gynecomastia requires a thorough Gynecomastia requires a thorough investigation for cause; including investigation for cause; including hormonal evaluation if indicatedhormonal evaluation if indicated

Treatment must address the causeTreatment must address the cause

ReferencesReferences Appelbaum, AH. “Mammographic Appearances of Male Breast Disease.” Appelbaum, AH. “Mammographic Appearances of Male Breast Disease.”

Scientific Exhibit 1999;19:599-68Scientific Exhibit 1999;19:599-68 Bagatell, C. “Androgens in Men – Uses and Abuses”. NEJM 1996;334:707-14Bagatell, C. “Androgens in Men – Uses and Abuses”. NEJM 1996;334:707-14 Braunstein, Glenn.Braunstein, Glenn. “Gynecomastia”. NEJM 2007;357:1229-35“Gynecomastia”. NEJM 2007;357:1229-35 Braunstein, Glenn.Braunstein, Glenn. “Gynecomastia”. NEJM 1993;328:490-95“Gynecomastia”. NEJM 1993;328:490-95 Braunstein, Glenn.Braunstein, Glenn. “Aromatase and Gynecomastia”. Endocrine-Related “Aromatase and Gynecomastia”. Endocrine-Related

Cancer 1999;6:315-24Cancer 1999;6:315-24 Carlson, H. “Gynecomastia”. NEJM 1980;303:795-99Carlson, H. “Gynecomastia”. NEJM 1980;303:795-99 Boccardo, F. “Evaluation of Tamoxifen and Anastrozole in the Prevention of Boccardo, F. “Evaluation of Tamoxifen and Anastrozole in the Prevention of

Gynecomastia and Breast Pain Induced byBicalutamide Monotherapy of Gynecomastia and Breast Pain Induced byBicalutamide Monotherapy of Prostate Cancer.” J Clin Onc 2005;23:808-15Prostate Cancer.” J Clin Onc 2005;23:808-15

Hands, L. “Gynaecomastia”. Br. J. Surg. 1991; 78:907-11Hands, L. “Gynaecomastia”. Br. J. Surg. 1991; 78:907-11 Harlan, WR “Secondard sex characteristics of boys 12-17 years of age; the Harlan, WR “Secondard sex characteristics of boys 12-17 years of age; the

U.S. Health Examination Survey.” J Pediatrics 1979;95:293-97U.S. Health Examination Survey.” J Pediatrics 1979;95:293-97 Hannekin, S. “Unilateral Pseudogynecomastia: A Novel Work-Related Hannekin, S. “Unilateral Pseudogynecomastia: A Novel Work-Related

Disease.” Ann Int Med 2004;140:497-98Disease.” Ann Int Med 2004;140:497-98 Hirshberg, B. “Ectopic LH Secretion and Anovulation”. NEJM 2003;348:312-Hirshberg, B. “Ectopic LH Secretion and Anovulation”. NEJM 2003;348:312-

1717 Larsen: Williams Textbook of Endocrinology, 10th edLarsen: Williams Textbook of Endocrinology, 10th ed

ReferencesReferences Lawrence, SE. “Beneficial effects of raloxifene and tamoxifen in the Lawrence, SE. “Beneficial effects of raloxifene and tamoxifen in the

treatment of pubertal gynecomastia.” J Pediatr 2004; 145:71. treatment of pubertal gynecomastia.” J Pediatr 2004; 145:71. Mignon, M. “Gynaecomastia and H2 antagonists.” Lancet 1982;ii:499Mignon, M. “Gynaecomastia and H2 antagonists.” Lancet 1982;ii:499 Nydick M. “Gynecomastia in adolescent boys.” JAMA 1961; 178:449–454Nydick M. “Gynecomastia in adolescent boys.” JAMA 1961; 178:449–454 Pearlman, G. “Gynecomastia, An Update.” The Endocrinologist 2006;16:109-Pearlman, G. “Gynecomastia, An Update.” The Endocrinologist 2006;16:109-

1515 Pitt, B et. Al. “The effect of spironolactone on morbidity and mortality in Pitt, B et. Al. “The effect of spironolactone on morbidity and mortality in

patients with severe heart failure.” NEJM 1999;341:709-17patients with severe heart failure.” NEJM 1999;341:709-17 Pitt, B et. Al. “Eplerenone, a selective aldosterone blocker, in patients with Pitt, B et. Al. “Eplerenone, a selective aldosterone blocker, in patients with

left ventricular dysfunction after myocardial infarction .” NEJM left ventricular dysfunction after myocardial infarction .” NEJM 2003;348:1309-212003;348:1309-21

Plourde, P. “Saftery and Efficacy of Anastrozole for the Treatment of Pubertal Plourde, P. “Saftery and Efficacy of Anastrozole for the Treatment of Pubertal Gynecomastia.” J Clin Endocrinol Metab 2004;89:4428-33Gynecomastia.” J Clin Endocrinol Metab 2004;89:4428-33

Rodriquez, LA. “Risk of gynaecomastia associated with cimetidine, Rodriquez, LA. “Risk of gynaecomastia associated with cimetidine, opeprazole, and other antiulcer drugs”. BMJ 1994;308:503-6opeprazole, and other antiulcer drugs”. BMJ 1994;308:503-6

Rose, L. “Pathophysiology of spironolactone-induced gynecomastia.” Ann Rose, L. “Pathophysiology of spironolactone-induced gynecomastia.” Ann Intern Med 1977;87:398-403Intern Med 1977;87:398-403

Scully, R. “Case Records”. NEJM 2000; 342:1196-1204Scully, R. “Case Records”. NEJM 2000; 342:1196-1204 Staiman VR. ”Tamoxifen for flutamide/finasteride-induced Staiman VR. ”Tamoxifen for flutamide/finasteride-induced

gynecomastia.” Urology 1997;50:929-933gynecomastia.” Urology 1997;50:929-933 Tseng, A. “Gynecomastia in testicular cancer patients. Prognostic and Tseng, A. “Gynecomastia in testicular cancer patients. Prognostic and

therapeutic implications.” Cancer 1985; 56:2534. therapeutic implications.” Cancer 1985; 56:2534. UpToDate.comUpToDate.com

gynecomastia. question 24 year-old male presents to pcp for painless enlargement of breasts for past...

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