19-Year-Old With Gynecomastia by bcs24005

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									19-Year-Old With
  Gynecomastia
     Anastassia Amaro, MD
 Fellow, Endocrinology and Metabolism
Washington University School of Medicine
          December 15, 2005
                 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
               Gynecomastia
is a benign enlargement of the male breast resulting
 from a proliferation of the glandular component of
                      the breast.
     Differential Diagnosis of
          Gynecomastia

Pseudogynecomastia
Breast carcinoma
Neurofibroma
Lipoma
Dermoid Cyst
             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
                         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.
            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
             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)
Androgen Action




      From Griffin, N Engl J Med 1992; 326:611-618
Structure of Estrogen Receptor
Distribution of Estrogen Receptors and Aromatase in
           the Male Reproductive System




                          From Rochira et al, Asia J Androl 2005; 7:3-20
Role of Estrogen and Aromatase in Male
              Physiology




                  Grumbach. Ann N Y Acad Sci 2004;1038:7-13
                              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)
            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
             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
                 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
                      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
                 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
   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
         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
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
        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
      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
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
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
 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
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
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
    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.
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
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
     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)
                 Gynecomastia in Hyperthyroidism – Proposed
                                Mechanisms


                                               Androstenedione
                 Testosterone




Secretion

                  Estradiol                       Estrone
Extraglandular
Formation
         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
Hyperthyroidism and Gonadal Dysfunction




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




                            Sperm Counts and Sperm
                            Motility in Hyperthyroidism




                    From Meikle, Thyroid 2004; 14 Suppl1:17-25
Thank You

								
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