DR. RICHARD JORDAN PROFESSOR OF MEDICINE AND PROGRAM DIRECTOR CHIEF, DIVISION OF ENDOCRINOLOGY AND METABOLISM J. H. QUILLEN VA MEDICAL CENTER & EAST TENESSEE STATE UNIVERSITY JOHNSON CITY, TN

MALE HYPOGONADISM

Secondary Hypogonadism (Hypogonadotrophic Hypogonadism) Kallmann Syndrome Idiopathic Gonadotrophin Deficiency Selective Gonadotrophin Deficiency Prader-Will Syndrome Acquired Gonadotrophin Deficiency (Continued)

Secondary Hypogonadism (Hypogonadotrophic Hypogonadism) Kallmann Syndrome Absent or Deficient GnRH (Mild to Severe) Eunuchoid with Variable Expression of Hypogonadism, Anosmia, or Hyposmia, R/G Color Blindness, Cleft Palate, GU Tract Abnormalities, Neurosensory Deafness Genetics:Sporadic, Dominant, Recessive, X-linked Etiology:Absent neural cell adhesion molecule (anosmin) in 0-14%, KAL Gene Point Mutation (Continued)

Secondary Hypogonadism (Hypogonadotrophic Hypogonadism ) Idiopathic Gonadotrophin Deficiency No Somatic Abnormalities, No Ansomia, No KAL, Gene Mutation, Abnormal GnRH Receptor in a Few Selective Gonadotrophin Deficiency Isolated LH Deficiency: “Fertile” Eunuch, Absence Virilization with Spermatogenesis Isolated FSH Deficiency: Somewhat Small Testis, Oligospermia to Azospermia, Normal Virilization (Continued)

Secondary Hypogonadism (Hypogonadotrophic Hypogonadism) Prader-Willi Syndrome Obesity, Hypotonia, Hypogonadotrophic Hypogonadism, Retardation, Small Hands and Feet (Continued)

Secondary Hypogonadism (Hypogonadotrophic Hypogonadism) Acquired Gonadotrophic Deficiency Prolactinoma Other Pituitary Tumors Hypothalamic Tumors Infiltrative Disorders Hemochromatosis Eosinophilic Granuloma Sarcoidosis

Clinical Evaluation History Diminished Libido, Weakness, Erectile Dysfunction, Behavior Abnormalities, Systemic Illness, Headache, Visual Changes, Multiple Hormone Deficiencies, Chemotherapy, Radiation Rx, Orchitis, Toxin Exposure, Anosmia, Family History of Delayed Puberty (Continued)

Clinical Evaluation Physical Examination Eunuchoid Proportions, Size of Testis, Gynecomastia, Characteristic Dysmorphic Features, Secondary Sex Characteristics Slow to Change

Laboratory Evaluation Gonadal Function Semen Analysis Sperm Count – 20 million/ml, 40 million/ejaculate, >50% normal motility, >30% normal morphology Testosterone—Total or Free? Decreased Binding—Obesity, Hypothyroidism, Acromegaly Increased Binding—Old Age, Cirrhosis, Thyrotoxicosis Testosterone Lower in the Afternoon Gonadotropins LH: Elevated with Leydig Cell Dysfunction FSH: Elevated with Germinal Cell Dysfunction or Leydig Cell Dysfunction Gonadotrophins: Normal or Low with Secondary Hypogonadism

Therapy Secondary Hypogonadism 1. HCG—1000u 3 times weekly HMG—75u 3 times weekly 2. GnRH pulses (pulse q 90 min) Primary Hypogonadism 1. Testosterone Ester Injection 2. Testosterone Patch—5 mg/day 3. Testosterone Gel—Upper Arms, Shoulders, Abdomen Side Effects Exacerbation of BPH, Occult Prostate Cancer, Erythrocytosis, Sleep Apnea

) Primary Hypogonadism (Hypergonadotrophic Hypogonadism) Klinefelter Syndrome XX Male (Sex Reversal) Noonan Syndrome (Male Turner Syndrome) Myotonic Dystrophy Congenital Anorchia (Vanishing Testis Syndrome) Sertoli-Cell-Only Syndrome Acquired Germinal Cell Aplasia Orchitis Chronic Illnesses (Continued)

Primary Hypogonadism (Hypergonadotrophic Hypogonadism) Klinefelter Syndrome 46 XXY, 46 XY/XXY, 48 XXXY Eunuchoid lower segment, Taller than Average, Gynecomastia, Gynecoid Features, Very Small Testis, Normal to Low Testosterone, FSH increase >LH, Modest Elevation of Estradiol, Severe Oligospermia to Azospermia Associated Conditions: COPD, Cancer of Breast, Germ Cell Tumors, Autoimmune Diseases, Diabetes Mellitus, Osteopenia, Mitral Valve Prolapse, Mental Slowness, Antisocial Behavior (Continued)

Primary Hypogonadism (Hypergonadotrophic Hypogonadism) XX Male (Sex Reversal) Translocation of the SRY gene, Shorter than Average, Normal Intelligence, Gynecomastia, Small Testis, Azospermia Noonan Syndrome (Male Turner Syndrome) 46 XY, Short Stature, Webbed Neck, Shield Chest, Small Testis, Impaired Spermatogenesis, May Have Low Testosterone Associated Conditions: Mental Retardation, Pulmonary Stenosis, Hypertrophic Cardiomyopathy, Tyrosine Phosphase Activation? (Continued)

Primary Hypogonadism (Hypergonadotrophic Hypogonadism) Myotonic Dystrophy Autosomal Dominant Inability to Relax Striated Muscle, Frontal Balding, Ptosis, Cataracts, Atrophy of Facial Muscles, Distal Muscle Wasting, Testicular Atrophy after Puberty Associated Conditions: Cardiomyopathy with Conduction Abnormalities, Type II Diabetes Mellitus, Mental Retardation, Decreased Myotonin (transfers phosphate to ATP) (Continued)

Primary Hypogonadism (Hypergonadotrophic Hypogonadism) Congenital Anorchcia (Vanishing Testis Syndrome) 46XY, No Discernable Testicular Tissue in Most, Bilateral Testicular Torsion in Utero? HCG Stimulation—Detect Testicular Remnants Sertoli-Cell-Only Syndrome 46XY, Germinal Cell Aplasia, FSH>LH Testosterone Normal Sertoli Cells Vacuolated—Functional Abnormality? (Continued)

Primary Hypogonadism (Hypergonadotrophic Hypogonadism) Acquired Germinal Cell Aplasia Chemotherapy, Radiation, Environmental Toxins (Dibromodichloralpropane) Orchitis Post-Pubertal Mumps: 40% have Orchitis, 40% with Orchitis have Varying Degrees of Testicular Atrophy, Sperm Count Lower in Most with Atrophy but True Impaired Fertility in 15% Autoimmune Orchitis: Type I and II endocrine deficiency Chronic Illnesses Cirrhosis, Chronic Renal Failure, Long-Term Glucocorticoid Therapy