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Male Hypogonadism

Male Hypogonadism

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Male Hypogonadism

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  1. Male Hypogonadism Michael Jakoby, MD/MA Clinical Associate Professor of Medicine Chief, Division of Endocrinology

  2. Case A 26 yo white male is referred due to sexual dysfunction. Since marriage 6 months ago, the patient has not always been able to achieve an erection sufficient for intercourse. He was sexually abstinent before marriage. Libido is “fair to poor.” Growth of pubic hair and shaving occurred between 15 and 17 years. Exercise tolerance was “good.” Testes have always been “small.” There was no head trauma, loss of smell, testicular trauma, testicular surgery, or treatment for cancer. The patient denied chronic illness or taking medication. Family history was unremarkable. Exam: 71 in (180 cm) 76 kg, armspan 181 cm crown to pubis 89 cm, pubis to floor 91 cm typical male muscle mass, body and pubic hair somewhat sparse, normal appearing phallus both testes descended, firm, NT, no masses, 3-4 cc

  3. Definition Decrease in one or both of the two major functions of the testes.

  4. Gonadal Axis

  5. Male Gonadal Function

  6. Male Puberty

  7. Clinical Features *Arm span > 2 cm longer than vertical height; lower body segment > 2 cm longer than upper body segment

  8. Screening for Androgen Deficiency The Endocrine Society recommends against screening for androgen deficiency in the general population • Infertility • Sellar mass, radiation, or surgery • Osteoporosis or low trauma fracture • HIV-associated weight loss • ESRD • COPD (moderate to severe) • Type 2 diabetes mellitus • Medications that effect testosterone production • Glucocorticoids • Opiates • Ketoconazle

  9. History • Symptoms onset • Testicular size • Breast enlargement • Behavioral abnormalities • Chemotherapy or radiation therapy • Alcoholism • Visual field defects • Medications

  10. Examination • Testicular size • Pubic hair • Gynecomastia • Muscle mass • Body proportions • Fundoscopy & visual fields screening

  11. Laboratory Testing

  12. Testosterone Measurements • Total testosterone (free + protein bound) is almost always an accurate measure of testosterone secretion • Free testosterone should be measured by equilibrium dialysis; analog methods commonly available give results proportionate to SHBG levels (Vermeulin A JCEM 84:3666) • Testosterone should be measured in the morning (~ 8 AM) due to diurnal variations in testosterone levels, especially in young men • Conditions that predispose to low SHBG levels: • Obesity (BMI > 40) • Senescence • Nephrotic syndrome • Cirrhosis • Anticonvulsants

  13. Testosterone in Obese Men Comparisons of total and free testosterone between morbidly obese men (BMI > 40) and age-matched controls. Glass AR et al. JCEM (1977) 45:1211

  14. Testosterone Secretion:Comparison of Young and Elderly Men Bremner WJ et al. JCEM (1983) 56:1278

  15. Standard Semen Analysis • Typically ordered for infertility w/u only • Normal specimen: • > 40 million sperm/ejaculate • > 50% motile; > 25% rapidly motile • > 50% normal morphology

  16. Klinefelter’s syndrome Gonadotropin receptor mutations Cryptorchidism Androgen biosynthesis disorders Varicocele Congenital anorchia Mumps orchitis Radiation Antineoplastic drugs Ketoconazole Glucocorticoid excess Trauma Testicular torsion Autoimmune orchitis Cirrhosis Chronic renal failure HIV infection Idiopathic DDx: Primary Hypogonadism Congenital Acquired

  17. Isolated hypogonadotropic hypogonadism Kallman’s syndrome DAX1 mutation GPR 54 mutation Leptin or leptin receptor mutations Gonadotrope receptor mutations Hypopituitarism Hyperprolactinemia Androgen therapy GnRH analog therapy Glucocorticoid therapy Critical illness Chronic illness Diabetes mellitus Opiates Pituitary mass lesions Infiltrative diseases Sellar surgery Sellar radiation DDx: Secondary Hypogonadism Congenital Acquired

  18. Case How would you evaluate this patient? Total testosterone: 134 ng/dL (176-781) Luteinizing hormone (LH): 26.3 mIU/mL (1.3-13.0) What is the initial diagnosis? Primary hypogonadism What is the next step in work up?

  19. Klinefelter’s syndrome Gonadotropin receptor mutations Cryptorchidism Androgen biosynthesis disorders Varicocele Congenital anorchia Mumps orchitis Radiation Antineoplastic drugs Ketoconazole Glucocorticoid excess Trauma Testicular torsion Autoimmune orchitis Cirrhosis Chronic renal failure HIV infection Idiopathic DDx: Primary Hypogonadism Congenital Acquired

  20. Evaluation of Men with Androgen Deficiency Confirmed low testosterone Check LH+FSH (SA if infertility) High gonadotropins – 1o Low/low nl gonadotropins – 2o Prolactin, other pituitary hormones, iron studies, sella MRI Karyotype

  21. Case How would you evaluate this patient? Total testosterone: 134 ng/dL (176-781) Luteinizing hormone (LH): 26.3 mIU/mL (1.3-13.0) What is the initial diagnosis? Primary hypogonadism What is the next step in work up? Karyotype: 47 XXY

  22. Klinefelter’s Syndrome • Incidence ~ 1/1,000 live male births • Extra X chromosome, usually 47 XXY • Phenotype strongly influenced by CAGn repeat in the androgen receptor gene • Manifestations • Hypogonadism • Gynecomastia • Behavioral disorders • Bronchiectasis/emphysema/bronchitis • Mediastinal germ cell tumors • Non-Hodgkin’s lymphoma • Diabetes mellitus • Lower extremity varicosities

  23. Gonadal Manifestations of Klinefelter’s Syndrome Gordon DL et al. Arch Intern Med (1972) 130:720

  24. Testosterone Replacement • Primary goal is to restore testosterone levels to the laboratory reference range • Prescribe only for patients with confirmed hypogonadism • Role in “treating” decline in testosterone levels with aging uncertain • Multiple preparations • Oral • Intramuscular • Transdermal • Buccal

  25. Oral Testosterone Preparations • Alkylated testosterone more slowly metabolized by liver than native testosterone • May not induce virilization in adolescents • Untoward effects • Cholestatic jaundice • Peliosis hepatis • Hepatocellular carcinoma

  26. Intramuscular Testosterone • Enanthate and cypionate esters of testosterone • Lipophilic, leading to sustained release from muscle depots • Side effects related to dosing or administration • Regimens of 100 mg q wk to 300 mg q 3 wks acceptable • Goal is a mid-cycle level near the middle of the laboratory reference range

  27. Intramuscular Testosterone Serum testosterone levels after a single 200 mg IM dose of testosterone enanthate. Snyder PJ et al. JCEM (1999) 51:1335

  28. Transdermal Testosterone • Patch (Androderm) • Apply to skin of upper arms and torso • Delivers 5 mg testosterone/24 hr in continuous manner • Approximately 1/3 of patients develop significant contact dermatitis • Gels (Androgel, Testim) • Apply to skin of upper arms and torso • Usually dosed as 5.0 g or 10.0 g of gel to deliver 50 mg or 100 mg testosterone, respectively in a continuous manner • Reports of contact dermatitis and gel odor uncommon

  29. Transdermal Testosterone Serum testosterone levels after single applications of a 5 mg Androderm patch and 5.0 g and 10.0 g testosterone gel doses. Snyder PJ et al. JCEM (1999) 51:1335

  30. Desirable Effects of Testosterone Therapy • Virilization (incompletely virilized men) • Increased libido and energy • Improved erectile function? • Increased muscle mass and strength (8-10 wks) • Increased bone mass (full effect ~ 24 mo)

  31. Untoward Effects of Testosterone Therapy • Pain at injection site (IM preparations) • Contact dermatitis (patch >> gel) • Acne or oily skin • Gynecomastia • Aggressive behavior (adolescents) • Short stature (adolescents) • Increased prostate volume/PSA • Urinary retention (BPH exacerbation) • Sleep apnea • Erythrocytosis

  32. Contraindications to Testosterone Therapy • Very high risk of adverse outcomes • Prostate cancer • Breast cancer • High risk of adverse outcomes • Undiagnosed prostate nodule • Unexplained PSA elevation • BPH with severe urinary retention • Erythrocytosis • NYHA Class III or IV heart failure

  33. Pre-treatment Screening • Digital rectal exam • History of urinary retention (urodynamic studies, bladder US PRN) • History of sleep apnea symptoms (polysomnography PRN) • PSA (urology referral if > 4 ng/mL) • CBC

  34. Treatment Monitoring • Serum testosterone • IM testosterone: midpoint between injections, level near middle of reference range • Patch: 3-12 hrs after applying new patch • Gel: timing not critical • Buccal pellet: immediately before or after new pellet • Prostate • DRE @ 3 months, then annually • PSA @ 3 months, then annually • Prostate biopsy if PSA > 4 ng/mL, PSA increases by > 1.4 ng/mL in 12 months, or PSA velocity > 0.4 ng/mL/yr • Red cell mass • CBC at 3 months, then annually • If Hct > 54%, stop therapy, monitor for return to reference range, then resume therapy at a lower dose

  35. Case How would you manage this patient? Androgel 5 g topically QD Counseling regarding infertility and extragonadal manifestations of Klinefelter’s syndrome Make patient aware of Klinefelter’s support groups

  36. Summary • Signs and symptoms of hypogonadism depend on when the condition occurs in development • Initial evaluation focuses on distinguishing between primary and secondary hypogonadism • Primary: LH elevated, testosterone low • Secondary: LH low, testosterone low • Goal of testosterone replacement is physiological testosterone levels and preservation of testosterone-dependent physiological functions