6/14/2010. GnRH=Gonadotropin-Releasing Hormone.

Transcription

1 Male Androgen Replacement Mitchell Sorsby, MD June 19, QUESTION # 1 Which of the following is not a symptom associated with low T levels? a) decreased libido b) erectile dysfunction c) depression d) nocturia e) fatigue QUESTION # 2 Which of the following is not an adverse effect of T therapy? a) polycythemia b) causes prostate CA c) worsening sleep apnea d) prostatism e) increased PSA level 1

2 QUESTION # 3 Which parameter does not need to be monitored with testosterone therapy? a) Comprehensive metabolic panel b) CBC c) PSA d) Digital prostate exam e) Testosterone level QUESTION # 4 Which of the following are not appropriate forms of Testosterone therapy? a) Oral b) Buccal tablets c) Transdermal patches d) Transdermal gel e) IM injection Primary Hypogonadism Secondary Combination 2

3 Testicular Due Due 6/14/2010 Primary Hypogonadism Testicular failure to produce testosterone Due to Klinefelter syndrome, cryptorchidism, vanishing testis syndrome, bilateral torsion, orchitis, orchiectomy, chemotherapy or toxic damage from radiation, alcohol, or heavy metals Fauci AS, Braunwald E, et al (eds). Harrison's Principles of Internal Medicine. 14th Edition. McGraw-Hill Book Company. New York Secondary Hypogonadism Hypothalamic-pituitary pituitary failure to stimulate testicular testosterone production Due to gonadotropin or GnRH deficiency (idiopathic or Kallman syndrome), pituitary- hypothalamic injury from tumors, trauma, or radiation Hyperprolactinemia GnRH=Gonadotropin-Releasing Hormone. Fauci AS, Braunwald E, et al (eds). Harrison's Principles of Internal Medicine. 14th Edition. McGraw-Hill Book Company. New York Combination Hypogonadism -Hypothalamic and testicular changes associated with: Aging Sickle cell disease Alcoholism Hemochromatosis Chronic illnesses Fauci AS, Braunwald E, et al (eds). Harrison's Principles of Internal Medicine. 14th Edition. McGraw-Hill Book Company. New York

4 Bound Free Unbound Free 6/14/2010 COMBINED DEFECT- DIAGNOSTIC DILEMMA Testosterone LH PRIMARY low high SECONDARY low low-nl COMBINED low low-nl Testosterone in Normal Males 2% free testosterone (unbound) 30% tightly bound to SHBG 2% free testosterone (unbound) and 68% loosely bound to albumin constitute the 70% of bioavailable testosterone SHBG=Sex Hormone-Binding Globulin. 68% loosely bound to albumin 1. AACE Hypogonadism Task Force. Endocri Pract. 2002;8: Winters SJ et al. Clin Chem. 1998;44: Testosterone in Normal Males Total Testosterone Bound testosterone: Albumin/SHBG (98%) 1 Free testosterone (2%) 1 Free Testosterone Unbound testosterone (2%) 1 Bioavailable Testosterone Free and albumin-bound bound testosterone (70%) 2 SHBG=Sex Hormone-Binding Globulin. 1. AACE Hypogonadism Task Force. Endocri Pract. 2002;8: Winters SJ et al. Clin Chem. 1998;44:

5 TESTOSTERONE MEASUREMENTS Total testosterone- accurate methodology but varies with SHBG levels. Bioavailable T- accurate methodology and avoids variations in SHBG binding Free T by equilibrium dialysis- accurate but time consuming and expensive CIRCADIAN RHYTHMICITY OF TESTOSTERONE SECRETION In young men testosterone levels are highest in the early morning and drop significantly in the late afternoon. This rhythmicity is attenuated in older men. Serum levels of testosterone have frequent spikes and nadirs. To diagnose hypogonadism in younger men early morning samples are needed. In older men the time of day of sampling is not important. Measurement of Serum Testosterone Levels Circulation Variation in Serum Testosterone in Normal Males Serum Testosterone (ng/dl) Young (23-28 yrs) Clock Time (hours) Bremner WJ et al. J Clin Endocrinol Metab.1983;56: Old (58-82 yrs)

6 Diagnostic Testosterone Testing Additional Tests: LH To ascertain whether cause is primary or secondary Serum prolactin High prolactin levels may suggest presence of pituitary tumor Tenover JL. Endocrinol Metab Clin North Am. 1998;27: LABORATORY TESTS Total T, LH, Prolactin- morning specimen Total T <200 ng/dl is definitely abnormal- if LH is not elevated obtain MRI of pituitary/hypothalamus Total T ng/dl /dl- check bioavailable T or free T by equilibrium dialysis. MRI if LH is not elevated or prolactin is increased Gonadal Effects of Aging Decline in testosterone production Decreased testosterone levels Increased SHBG levels Decreased free T levels Tenover JL. Endocrinol Metab Clin North Am. 1998;27:

7 DECLINING TESTOSTERONE LEVELS WITH AGING Results from a dual defect in Leydig cell function and the hypothalamic-pituitary pituitary axis. Peripheral- decreased Leydig cell number and response to HCG Central- in older men the LH pulses are diminished. The central defect lies at the level of the hypothalamus as demonstrated by the normal pituitary response to gonadotropin releasing hormone administration. LH and Prolactin are usually normal DECLINING TESTOSTERONE LEVELS WITH AGING Testosterone levels in studies decrease by approximately 1-1.5% 1.5% per year in men over 40 years of age 1. Haren MT et al. Climacteric. 2002;5(1): Harman SM et al. J Clin Endocrinol Metab. 2001;86(2): WHO DO WE SCREEN FOR HYPOGONADISM? 7

8 The ADAM Questionnaire 1. Do you have a decrease in libido (sex drive)? 2. Do you have a lack of energy? 3. Do you have a decrease in strength and/or endurance? 4. Have you lost height? 5. Have you noticed a decreased enjoyment of life? 6. Are you sad and/or grumpy? 7. Are your erections less strong? 8. Have you noticed a recent deterioration in your ability to play sports? 9. Are you falling asleep after dinner? 10. Has there been a recent deterioration in your work performance? (Note: Positive questionnaire result is defined as a yes answer to questions 1 or 7 or any 3 other questions.) Morley JE. J Gend Specif Med. 2001;4(2): PHYSICAL EXAMINATION Decreased muscle mass Decreased body hair Gynecomastia Testicular atrophy TESTOSTERONE REPLACEMENT THERAPY: Risks & Concerns 24 8

9 Increased Increased 6/14/2010 Goals and Benefits of Testosterone Therapy Restore libido and improve erectile function 1-3 Improve lean body mass 2,3 Decrease total body fat 3 Improve bone density 1,2 Improve psychological disposition 1-3 Improve energy level 3 Improve mood/sense of well being 2,3 1. Hypogonadism Task Force. Available at: Accessed on June 22, Tenover JL. Endocrinol Metab Clin North Am. 1998;27: Wang C, Swerdloff RS, Iranmanesh A, et al. JCEM. 2000;85: Concerns of Testosterone Replacement Therapy Polycythemia Increased red blood cell mass Increased hemoglobin and hematocrit Increases in PSA levels possible prostate changes Gynecomastia Sleep apnea PSA=Prostate-Specific Antigen. Morales A et al. J Urol. 2000;163: Concerns of Testosterone Replacement Therapy A PSA increase of 1.5 ng/dl in 2 years,.75 ng/dl/yr for 2 consecutive years or an absolute level >4ng/dl is cause for concern and urologic evaluation 9

10 Infrequent Boost PSA, No Testosterone Supraphysiologic Discomfort 6/14/2010 Concerns of Testosterone Replacement Therapy Prostate Cancer PSA, a marker for prostate cancer, may change with testosterone replacement therapy 1 No evidence that normalization of testosterone with testosterone replacement therapy induces prostate cancer 1 Testosterone replacement therapy is contraindicated in persons with prostate cancer 2 PSA=Prostate-Specific Antigen. 1. Gersten B et al. J Androl. 2002;23(6); Vermeulen A. J Clin Endocrinol Metab. 2001;86(6): Testosterone Therapy Delivery Systems Oral tablets Intramuscular injections Transdermal patch Transdermal gel Applied to upper arms, shoulders, and abdomen Buccal testosterone Testosterone pellets Winters SJ. Arch Fam Med. 1999:8; Testosterone Replacement Therapy: Injectable Advantages Infrequent dosing Boost effect Cost Limitations Supraphysiologic testosterone levels initially Sub-therapeutic levels at end of injection cycle Discomfort of injection Roller-coaster effect Morales A et al. J Urol. 2002;163:

11 High High May C 6/14/2010 Testosterone Replacement Therapy: Transdermal Patches Advantages Noninvasive application Normalization of serum testosterone levels Once-a-day dosing Convenient application sites Limitations rate of dermal reactions discontinuation rate be inconvenient to apply min levels on treatment below baseline trough levels 1 Cost* 1. Steidle C et al. J Clin Endocrinol Metab [In press.]. TESTOSTERONE REPLACEMENT THERAPY- BUCCAL TABLETS Advantages Easy application No skin irritation Limitations Twice daily application Gum irritation Little clinical experience Cost Striant (testosterone buccal system) 11

12 Once-a-day Normalizes Convenient Potential 6/14/2010 Testosterone Replacement Therapy: Transdermal Gels Advantages dosing testosterone levels within 24 hours application sites: shoulders and upper torso Limitations for transfer to partner or child Cost** AndroGel Recommended Application Sites Abdomen Shoulders Upper arms Unimed Pharmaceuticals, Inc. AndroGel (testosterone gel) 1% CIII product information. PATIENT MONITORING Baseline- Breast exam (gynecomastia), DRE, PSA, hematocrit Followup- DRE, PSA, hematocrit at 3,6 and 12 months and annually thereafter. Decrease dosage or discontinue therapy if- Hct >54% Urologic evaluation if- increase in PSA of >1.4 ng/ml between 2 individual measurements or 1.5 ng/ml over 2 years Andropause consensus conference

13 QUESTION # 1 Which of the following is not a symptom associated with low T levels? a) decreased libido b) erectile dysfunction c) depression d) nocturia e) fatigue QUESTION # 2 Which of the following is not an adverse effect of T therapy? a) polycythemia b) causes prostate CA c) worsening sleep apnea d) prostatism e) increased PSA level QUESTION # 3 Which parameter does not need to be monitored with testosterone therapy? a) Comprehensive metabolic panel b) CBC c) PSA d) Digital prostate exam e) Testosterone level 13

14 QUESTION # 4 Which of the following are not appropriate forms of Testosterone therapy? a) Oral b) Buccal tablets c) Transdermal patches d) Transdermal gel e) IM injection 14