1. 19-Year-Old With
Gynecomastia
Anastassia Amaro, MD
Fellow, Endocrinology and Metabolism
Washington University School of Medicine
December 15, 2005

2. Case report
Cc: 19 yo WM with bilateral breast enlargement
for 3 months.
First unilateral, then bilateral within a month
Pain and tenderness
Usual state of health

3. Gynecomastia
is a benign enlargement of the male breast resulting
from a proliferation of the glandular component of
the breast.

4. Differential Diagnosis of
Gynecomastia
Pseudogynecomastia
Breast carcinoma
Neurofibroma
Lipoma
Dermoid Cyst

5. True Gynecomastia
Result of absolute or relative estrogen excess
50% idiopathic
Physiologic in:
Neonatal Period
Resolves within wks (Santen, Endocrinology vol. 3: 2335-2341, 2001)
Puberty
60% by age 14
Resolves within 3 yrs (Santen, Endocrinology vol. 3: 2335-2341, 2001)
>60 years of age

6. Sex Hormone Production in Males
Estradiol Estron
Extraglandular 1
Tissues 2 2
1
Testosterone Androstenedione
Testosterone Androstenedione
Circulation
Estradiol Estrone
Steroid- Cholesterol
Leydig
Secreting Cell Pregnenolone
Tissues Progesterone Adrenal
Testis
17α-Hydroxyprogesterone
1- 17β-hydroxysteroid dehydrogenase
Androstenedione
2 – aromatase 1
Testosterone
2
Modified from Braunstein, End-Rel Cancer
Estradiol
1999; 6:315-324.

7. Androgen-Estrogen Dynamics in Normal Men
8% Androstenedione
Testosterone
5200 mcg/day 5% 3000 mcg/day
0.3% 1.6%
Secretion Testes, 6
From Testosterone, 17 From Estradiol, 21
93%
Extraglandular From Androstendione, 45
Formation From Estrone, 22 49%
Estradiol, Estrone,
45 mcg/day 66 mcg/day
From MacDonald et al. J Clin Endocrinol Metab 1979; 49:905-916

8. Plasma Testosterone
2% free
44% bound to SHBG
54% bound to albumin and other proteins
(Dunn et al., J Clin Endocrinol Metab 1981; 53(1):58-68)
~50% active fraction
(Partridge, Clin Endocrinol Metab 1986; 15(2):259-78)

9. Androgen Action
From Griffin, N Engl J Med 1992; 326:611-618

10. Structure of Estrogen Receptor

11. Distribution of Estrogen Receptors and Aromatase in
the Male Reproductive System
From Rochira et al, Asia J Androl 2005; 7:3-20

12. Role of Estrogen and Aromatase in Male
Physiology
Grumbach. Ann N Y Acad Sci 2004;1038:7-13

13. Aromatase
Aromatase P450 enzyme: Cyp19 gene, located on chromosome 15.
(Means et al, J Biol Chem 1989; 264:19385-19391)
Activity demonstrated in testes, brain, skin fibroblasts, adipocytes,
breast stromal cells. (Simpson et al. 1994, Sasano et al. 1996)

14. Androgen-Estrogen Dynamics in Normal Men
8% Androstenedione
Testosterone
5200 mcg/day 5% 3000 mcg/day
0.3% 1.6%
Secretion Testes, 6
From Testosterone, 17 From Estradiol, 21
93%
Extraglandular From Androstendione, 45
Formation From Estrone, 22 49%
Estradiol, Estrone,
45 mcg/day 66 mcg/day
From MacDonald et al. J Clin Endocrinol Metab 1979; 49:905-916

15. Gynecomastia: Deficient Testosterone Formation
Testosterone Androstenedione
Secretion
Extraglandular Estradiol Estrone
Formation
Examples: Primary Gonadal Failure, congenital
Kleinfelter’s, Hermaphroditism
Primary Gonadal Failure, acquired
Viral Orchitis, Granulomatosis
Hypothalamic or Pituitary Disease
From Griffin and Wilson, Williams Textbook of Endocrinology, Tenth Edition,18:709-769, 2003

16. Gynecomastia: Increased Estrogen Secretion
Testosterone Androstenedione
Secretion Estradiol
Estrone
Extraglandular
Formation
Examples: Leydig Cell and Sertoli Cell Tumors
True Hermaphroditism
HCG-Secreting Tumors
From Griffin and Wilson, Williams Textbook of Endocrinology, Tenth Edition,18:709-769, 2003

17. Gynecomastia: Increased Extraglandular
Estrogen Formation - Increased Substrate
Testosterone Androstenedione
Secretion
Extraglandular Estradiol Estrone
Formation
Examples: Adrenal Tumors
Congenital Adrenal Hyperplasia
17ß-HSD 3 Deficiency
Hyperthyroidism, Liver Disease
From Griffin and Wilson, Williams Textbook of Endocrinology, Tenth Edition,18:709-769, 2003

18. Increased Extraglandular Estrogen Formation –
Increased Aromatase Enzyme
Testosterone Androstenedione
Secretion
Extraglandular
Estradiol Estrone
Formation
Examples: Hereditary Increase
Liver Carcinoma
Obesity, Hyperthyroidism
From Griffin and Wilson, Williams Textbook of Endocrinology, Tenth Edition,18:709-769, 2003

19. Prolactin and Gynecomastia
Prolactin is normal in gynecomastia.
No gynecomastia in males with hyperprolactinemia
unless testicular failure due to pituitary mass effect
or LH suppression.
Prolactin has no role in Gynecomastia.
From Griffin and Wilson, Williams Textbook of Endocrinology, Tenth Edition,18:709-769, 2003

20. Drugs and Gynecomastia
Estrogens and Estrogen Mimetics Drugs That Inhibit Testosterone
Estrogen (incl. topical, phyto-, and Action
environmental) Spironolactone
Digitalis Cimetidine, Ranitidine
Drugs That Enhance Endogenous Antiandrogens (cyproterone,
Estrogen Formation flutamide, zanoterone)
HCG Unknown Mechanism
Clomiphene citrate Protease Inhibitors, Isoniazid
Drugs That Inhibit Testosterone CaCB, ACE-I, Methyldopa, Amio
Synthesis Omeprazole
Ketoconazole Diazepam, Tricyclic Antidepresants
Alkylating Agents Theophylline
Spironolactone
From Griffin and Wilson, Williams Textbook of Endocrinology, Tenth Edition,18:709-769, 2003

21. Diagnostic Evaluation of Gynecomastia
History
Duration of breast enlargement
Presence of breast pain or tenderness
Drug history (prescription, over-the-counter,
occupational, or recreational)
Sexual functioning
Changes in virilization
Changes in weight
Symptoms of hyperthyroidism

22. Case Report - History
Puberty completed by age 15
Duration of breast enlargement 3 months
Presence of breast pain or tenderness yes
Drug history (prescription, OTC, or recreational) none
Sexual functioning normal
Changes in virilization none
Changes in weight none
Symptoms of hyperthyroidism tremor, ↑ perspiration
NO palpitations, anxiety, changes in hair, appetite, or
bowel habits

23. Case Report – History
PMH: elevated BP in PCP office, MVP
SHx: student, no tobacco, social ETOH,
marijuana x 5 total, no soy products
FH: Graves disease in mother, HTN in father
Allergies: none
Medications: none

24. Diagnostic Evaluation of Gynecomastia
Physical Examination
Thyroid and signs of thyroid hormone excess
Breast examination, suspicious findings suggestive of
malignancy
Abdominal examination for possible adrenal mass or
hepatomegaly
Examination of genitalia, testicular size, testicular
mass
Degree of virilization: body hair, voice, muscles

25. Case Report- Physical Examination
BP 140/75, HR 82, RR 14, wt 157 lbs
Gen: NAD, physically fit
HEENT: no exophthalmos, no lid lag
Thyroid: palpable, slightly enlarged, soft, no nodules, no LAD
Chest: bilateral tender mobile rubbery masses extending
concentrically from the nipples, 2 cm in diameter, no LAD
Heart: RRR, soft systolic murmur
Abdomen: no organomegaly
Neuro: DTR brisk
Genitalia: Tanner 5, testicular volume 20 ml, no masses
Virilization: appropriate for age

26. Diagnostic Evaluation of Gynecomastia
Laboratory evaluation
Serum creatinine
Liver enzymes
Serum total and free testosterone (T)
LH, FSH
Estradiol (E2)
TSH, free thyroxine (FT4)
Beta-HCG
Serum DHEA-S

27. Case Report – Laboratory Evaluation
CMP – normal Reference Range
Total T 1820 300-950 ng/dl
Free T 29.1 9.0-30.0 ng/dl
LH 7.0 1.5-9.0 IU/L
E2 80 10-50 pg/ml
TSH <0.02 0.4-6.2 mcIU/ml
FT4 2.8 0.9-1.8 ng/dl
Beta-HCG <5.0 0-5 IU/L
DHEA-S 2.96 1.25-6.19 mcg/ml

28. Case Report – Diagnosis & Treatment
24-hour thyroid uptake of I-131 52% (normal
range 10-30%)
Ds: Diffuse Toxic Goiter (Graves’ Disease)
Rx: 9.8 mCi of I-131

29. Case Report – Follow-up
8 wks post I-131 Rx
Weight gain: 2 lbs
Perspiration and tremor have improved.
BP 135/80
DTR: normal
Gynecomastia has resolved.

30. Case Report – Follow-up Labs
At Ds 8 wks FU Reference Range
Total T 1820 846 300-950 ng/dl
Free T 29.1 21.9 9.0-30.0 ng/dl
LH 7.0 4.4 1.5-9.0 IU/L
E2 80 49 10-50 pg/ml
TSH <0.02 <0.02 0.4-6.2 mcIU/ml
FT4 2.8 0.9 0.9-1.8 ng/dl

31. Gynecomastia in Hyperthyroidism
Hyperthyroidism accounts for 2% of all adult
gynecomastia.
Gynecomastia as the presenting manifestation of
hyperthyroidism is rare.
From Ismail and Barth, Ann Clin Biochem 2001; 38(6):596-607

32. Gynecomastia in Hyperthyroidism –
Proposed Mechanisms
Direct stimulation of peripheral aromatase
(Southern et al. J Clin Endocrinol Metab 1974; 38:207-14)
Stimulation of peripheral aromatase by
increased LH (Southern et al. J Clin Endocrinol Metab 1974;
38:207-14)
Increased Androstenediol and DHEA-S
production (Tagawa et al. Endocr J 2001; 48(3):345-54)

33. Gynecomastia in Hyperthyroidism – Proposed
Mechanisms
Androstenedione
Testosterone
Secretion
Estradiol Estrone
Extraglandular
Formation

34. Hormone Levels in Hyperthyroid Men
N Total T Free T E2 LH DHEAS ADIOLS
Kidd et al. 7(2) 1008±104 13 ±2.4 104 ±16 15.5 ±1.5
1979
Chan et al. 1(1) 1339 nl
1999
Abalovich 25(6) 930 ±33 62 ±25 7.8 ±4.7
et al. 1999
Tagawa et 9(?) 7.43 ±3.91 1.49 ±0.69
al. 2001
1820 29.1 80 7.0 2.96
Normal 300-950 9.0-30.0 10-50 1.5-9.0 1.25-6.19 0.01-0.69
Range ng/dl pg/ml pg/ml IU/L mcg/ml micromol/l

35. Hyperthyroidism and Gonadal Dysfunction
From Meikle, Thyroid 2004; 14 Suppl1:17-25

36. Hyperthyroidism and Gonadal Dysfunction
The correlation of FT4
with free T area under
the curve after HCG
administration and LH
area under the curve
after GnRH
administration
From Meikle, Thyroid 2004; 14 Suppl1:17-25

37. Hyperthyroidism and Gonadal Dysfunction
Sperm Counts and Sperm
Motility in Hyperthyroidism
From Meikle, Thyroid 2004; 14 Suppl1:17-25

38. Thank You