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Hypogonadism

Hypogonadism. Androgens. Testosterone: Made primarily in testes Most potent androgen Converted to Dihydrotestosterone or estrogen DHEA Made in adrenals Less potent Can be converted to testosterone in periphery. Testosterone in Men. Needed for appropriate sexual development

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Hypogonadism

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  1. Hypogonadism

  2. Androgens • Testosterone: • Made primarily in testes • Most potent androgen • Converted to Dihydrotestosterone or estrogen • DHEA • Made in adrenals • Less potent • Can be converted to testosterone in periphery

  3. Testosterone in Men • Needed for appropriate sexual development • Normal skeletal formation and maintenance • Normal bone marrow function • Normal muscular development and maintenance • Sense of well being, libido, potency

  4. Production and Regulationof Testosterone Hypothalamus GnRH Free T 2% Albumin- bound T 38% Pituitary FSH Testosterone LH Testis SHBG-bound T 60% Testosterone T = testosterone Only 2% is free testosterone and 98% is bound Sperm Adapted from Bagatell CJ, Bremner WJ. N Engl J Med. 1996;334:707-715. Adapted from Braunstein GD. In: Basic & Clinical Endocrinology. 5th ed. Stamford, Conn: Appleton & Lange; 1997:403-433.

  5. Definition of Hypogonadism • Hypogonadism can be defined as a reduction in testosterone production Primary: testicular failure Secondary: hypothalamic or pituitary dysfunction Combined: decreased pulsatility of gonadotropins plus decreased Leydig cell response • Congenital or acquired • May be multifactorial: aging, disease, habits, medication Winters SJ. Arch Fam Med. 1999;8:257-263. Tenover JL. Endocrinol Metab Clin North Am. 1998;27:969-987. Petak SM, et al. AACE Clinical Practice Guidelines. Available at: http://www.aace.com/clin/guidelines/hypogonadism.html.

  6. 5% of men are currently treated Prevalence of Hypogonadism 4 to 5 Million Men With Hypogonadism Adapted from US Food and Drug Administration Updates. Skin patch replaces testosterone. Available at: http://www.fda.gov/fdac/departs/196_upd.html.

  7. Primary testicular failure Hypogonadotropic hypogonadism (Kallmann’s syndrome, pituitary adenoma) Trauma Idiopathic Obesity Severe systemic illness (including HIV) Medications Changes in GnRH, prolactin, cortisol, and thyroid hormones Normal aging Causes of Hypogonadism Winters SJ. Arch Fam Med. 1999;8:257-263. Tenover JL. Endocrinol Metab Clin North Am. 1998;27:969-987.

  8. Primary Hypogonadism • Primary: Due to inability of testes to make testosterone • See high LH and FSH • Most common form • Toxins like chemotherapy, XRT • Klinefelters Syndrome (47XXY): • most common cause, 1 in 500 births • see small testes, gynecomastia, and azoospermia • Mumps orchitis • Drugs: ketoconazole • Injury/torsion

  9. Klinefelter’s

  10. Secondary Hypogonadism • Secondary: Due to abnormality of hypothalamus or pituitary • Low or normal LH and FSH along with low testosterone Secondary to severe illness or anabolic steroids most common causes • Kallman Syndrome: Hypothalamic inability to make GnRH. Associated with anosmia • Infiltrative disorders: Sarcoidosis, Langerhans histiocytosis, hemochromatosis • Prolactinoma, other tumors • Trauma, irradiation

  11. Effect of Age of Onset • Neonatal Period: Cryptorchidism, microphallus, ambiguous genitalia • Pre-Adolescence: Lack of secondary sex characteristics, Eunuchoidal body habitus, gynecomastia, pre-pubertal testes (<4 ml) • Adult: Infertility, decreased libido/potency, decreased energy/muscle mass, decreased bone density, maybe decrease in testicular size (NL teste=15-20 ml) or consistency

  12. Who to screen? • General population screening not recommended • Look for pts with high risk conditions • Can use screening questionnaire

  13. Endocrine Society Clinical Practice Guideline, 2006

  14. Low Testosterone Quiz

  15. ADAM Questionnaire Validation • Study of 316 male Canadian physicians • Results demonstrated High sensitivity (88%) Low specificity (60%) • Largely due to questions that identify persons with depression • 12 of 13 patients showed improved ADAM scores after 3 to 4 months of testosterone treatment Morley JE, et al. Metab. 2000;49:1239-1242.

  16. Signs and Symptoms of Low Testosterone in the Adult Male • Loss of libido and erectile dysfunction • Mood changes • Fatigue • Osteoporosis • Loss of muscle mass and strength • Some regression of secondary sexual characteristics • Oligospermia or azoospermia Tenover JL. Endocrinol Metab Clin North Am. 1998;27:969-987. Petak SM, et al. AACE Clinical Practice Guidelines. Available at: http://www.aace.com/clin/guidelines/hypogonadism.html.

  17. Evaluation • Good H&P: ask about puberty and development of secondary sex characteristics, libido, potency, hx of congenital defects, anosmia, orchitis, drugs. • Look for body habitus, gynecomastia, degree of virilization, testicular volume

  18. Testosterone Assay • Important to get an AM sample--diurnal variation • Serum Total Testosterone (free plus protein-bound) • Bound to SHBG (tightly) and Albumin • In house assay 241-827 ng/dL • Serum Free Testosterone (nonprotein-bound) • 2% of total testosterone • Mail out 35-155 pg/dL

  19. Endocrine Society Algorithm Endocrine Society Clinical Practice Guideline, 2006

  20. Treatment • If don’t desire fertility, can treat with testosterone • Don’t use oral testosterone (methyltestosterone) • Have variable availability • High risk for liver toxicity • Testosterone enanthate or cypionate, IM injection of 200 mg q2 weeks • Injection less physiologic

  21. Testosterone Enanthate

  22. Testosterone levels after injection

  23. Testosterone Patch • Androderm 5 mg transdermal system • Used to have trans-scrotal system, but not real popular • Attains adequate, stable levels, but can have problems with skin reactions and patches falling off. • I usually start with one patch qd and check T level after 3-4 weeks. Goal is to get in mid-normal range (>400)

  24. Androderm Patch

  25. Androderm Blister

  26. Androderm Profile

  27. Topical Testosterone Gel • Container of hydroalcoholic gel that is rubbed on upper body. Dissolves quickly • Rarely causes skin irritation • Attains steady levels • High pt satisfaction • Potential for skin-to-skin transfer

  28. Foil Packet or Pump One packet = 4 pumps

  29. Where to apply Androgel

  30. Androgel Profile

  31. Testim • Other topical testosterone gel • Apply to upper body • Has slight musky/baby powder odor, but doesn’t seem to bother pts • Claims to have 30% higher absorption than androgel

  32. Serum levels with Testim

  33. Transbuccal Testosterone • Striant: transbuccal 30 mg tablet that is placed above incisor on gums • Dosed every 12 hours • Achieves therapeutic levels • No dose titrations

  34. Striant Serum Levels

  35. Testosterone Pellets • Testopel is a new product in US • Pellets of 75 mg of testosterone • Implanted under subq tissue of hip • 3-6 pellets at a time, and good for 3-6 months

  36. Desired Fertility • Testosterone replacement will cause testes to get smaller and there will be no sperm production • If have functional testes, and problem is hypothalamic or pituitary in origin, can treat with hCG (LH) +/- FSH. Can also use pulsatile GnRH • This will increase intra-testicular testosterone levels, which will them lead to spermatogenesis

  37. Monitoring Testosterone Therapy • Goal is to get testosterone in mid-normal range (>400) • Do not use in pts with androgen dependent malignancies: Prostate, breast • Monitor Hct for polycythemia • Monitor PSA and DRE • Can exacerbate sleep apnea • No need to monitor lipids and LFTs—mostly with older oral formulations • Can develop gynecomastia

  38. Testosterone Therapy andPossible Prostate Changes • Increases risk of BPH • Increases risk of PSA rising • Increases in prostate volume • Stimulates growth in previously undiagnosed tumors • No data that it causes prostate cancer • Need to follow PSA at 3,6, and 12 months, and then annually. If increase >1.5 per yr or >4, refer to Urology. Hajjar RR, et al. J Clin Endocrinol Metab. 1997:82;3793-3796. Basaria S, Dobs AS. Drugs Aging. 1999;15:131-142.

  39. DM and Hypogonadism • Higher incidence of low testosterone in men with type 2 and to a lesser extent type 1 DM • Also seen in men with metabolic syndrome • Symptoms of DM and hypogonadism overlap, so may not be checked • Need to see if testosterone supplementation improves insulin resistance and glycemic control

  40. Effects of Treatment • 132 hypogonadal men age 19-68 were treated with topical testosterone for 3.5 years • Measured effects on body composition, mood, strength, lipids, sexual function, hematocrit Wang, et al. JCEM, May 2004, 89 (5):2085-2098

  41. Effect of Body Mass

  42. Effect on BMD

  43. Effect on Lipids

  44. Effect on Hematocrit

  45. Effect on Mood

  46. Effect on Erections

  47. Effect of Sexual Activity

  48. Effect on Prostate • One pt developed lower urinary tract sxs and required TURP • PSA increased from 0.85 to 1.11 • 7 pts PSA increased to >5.5 • 3 pts found to have prostate cancer • Incidence in pts >60 y/o=7.7% • Need to follow older pts closely

  49. Androgen Deficiency with Aging

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