1. Treatment of The Hypogonadal Male William Abeyta MD Associate Professor of Medicine AVAH/UNM SOM

2. OBJECTIVES Understand the clinical features of male hypogonadism. Discuss possible causes. Interpret laboratory tests and how to order them in different clinical scenarios. Review and describe the hypothalamic- pituitary-testicular axis. Understand general principles of treatment

3. OBJECTIVES Describe the various testosterone preparations. Understand the monitoring required when using testosterone replacement. Identify complications of treatment.

4. Why do we need testosterone? In men, testosterone plays a key role in the development of male reproductive tissues such as the testis and prostate as well as promoting secondary sexual characteristics such as increased muscle, bone mass, and the growth of body hair. In addition, testosterone is essential for health and well-being as well as the prevention of osteoporosis.

7. HISTORY Testosterone first used clinically in 1937, only 2 years after it’s Nobel Prize-winning discovery. Testosterone prescribing is escalating at startling rates creating a nearly $2 billion annual market. Surging off-label use (anti-aging, sexual tonic, bodybuilding or doping.

8. HYPOGONADISM Defined as the failure of the testes to produce androgen, sperm, or both. Testosterone production decreases with advancing age: 20% of men older than 60 and 30-40% of men older than 80 have serum testosterone levels that would be subnormal in their younger male counterparts.

9. Case I 82 yo male presented to his new PCP with a chief complaint of back pain. The pain began suddenly when he helped move a pool table at the senior center one month prior to this visit. Despite worsening pain to the point that he could no longer walk very well, he had refused to come in for evaluation. He had no neurologic/bowel/bladder complaints

10. Case I Meds: APAP, viagra. Tobacco: 1PPD x 65 years ETOH: none x 5 years, formerly heavy use PMH: 1. Right hip fracture with ORIF 2 years ago 2. Esophageal stricture with multiple dilations in the past. FH: neg for osteoporosis that he was aware of.

11. Case I PE: normal vitals Neck: no nodes or thyromegaly Lungs: decreased BSs throughout CV: RRR without M/R/G Abd: soft without hepatosplenomegaly or masses Back: Marked thoracic kyphosis with tenderness at T12 and L1 Testicles: 5cm bilat, normal pubic hair CXR: Hyperinflation Thoracic and lumbar spine films: compression fractures of T12 and L1 appearing acute.

12. Lab: Hct 38, MCV 95, nl WBC/plts Calcium 9.2 SPEP neg for paraprotein PSA <.03 Normal TSH/prolactin Free testosterone 0.3 (11-25) Total testosterone 32 (241-827) LH 14.1 (1-7) FSH 61.2(1.4-15) DXA: >4SD hip&spine PTH normal

13. Case II 66 year-old male presented to his resident MD for general medical f/u. He had been on testosterone injections for 2 years for primary hypogonadism. His last Hct was one year prior and had been 50. The patient complained of fatigue, headaches, and dizziness. On exam his face appeared very flushed. Lab testing showed a Hct of 62%.

14. Hypogonadism Low levels of testosterone along with other specific signs and sxs. (diminished libido, ED, reduced muscle mass/bone density, depression, anemia) Affects 2-4 million males in the US.

15. Hypogonadism Only 5% of men currently receive rx Recent interest in rx d/t media attention, marketing of new preparations, “desire of baby boomers” to maintain vigor and health into their more mature years. Considerable controversy regarding indications for testosterone supplementation in aging males.

16. Hypogonadism No large-scale, long-term studies yet initiated to assess risks and benefits of testosterone- replacement rx in part d/t theoretical risk of possible stimulation of prostate cancer by testosterone. It is estimated that a study would need to include 6000 elderly hypogonadal men randomly assigned to receive testosterone or placebo for 6 years in order to determine whether rx increases risk of prostate cancer by 30%. Snyder.Hypogonadism in Elderly Men-What To Until the Evidence Comes.N Engl J Med 2004;350:440-442

18. Gonadotrophins-FSH, LH Secreted by gonadotrophs in the anterior pituitary gland. FSH and LH secreted in pulsatile fashion. (pulsatile LHRH release results in pulsatile LH and FSH release). FSH has a longer half-life so levels fluctuate less throughout the day. Regulate testicular and ovarian function.

19. Testicular Effects of FSH and LH LH controls testosterone production by Leydig cells. FSH in conjunction with intratesticular testosterone stimulates seminiferous tubules to produce sperm. FSH and LH required for sperm production but only LH necessary for testosterone production.

20. The Testes 60% of testicular volume accounted for by seminiferous tubules. Prepubertal testis 2cm in length and 2ml in volume. Testes average 4.6cm in length in adults but range from 3.5-5.5 cm according to Harrisons Textbook of Medicine. 4-7cm in UpToDate.

21. Testes Advanced age does not influence testicular size. (therefore significance of small testes is the same at all ages of the adult) Testis size varies among ethnic groups. Asian men have smaller testes than western Europeans, independent of differences in body size.

25. Serum Testosterone Levels Diurnal rhythm. Values are 30% higher near 8am vs later in the day. Normal range varies among laboratories. Usual range for young men is 300-1000ng/d. In general values < 220-250 are clearly low in most laboratories. Values 250-350 should be considered borderline low.

26. Signs and Symptoms of Hypogonadism 1.Diminished libido 2.Erectile dysfunction 3.Difficulty achieving orgasm 4.Diminished intensity of orgasmic experience 5.Diminished sexual penile sensation

27. Signs and Symptoms of Hypogonadism Other 1.Diminished energy/sense of well being 2.Increased fatigue 3.Depressed mood 4.Anemia 5.Diminished bone density/muscle mass

28. Risks of Testosterone- Replacement Therapy 1.Coronary Artery Disease: few if any data support a causal relation between higher testosterone levels and heart disease. High testosterone levels may actually have a favorable effect on the risk of CV disease. Studies have not demonstrated an increased incidence of CV disease or events such as MI, stroke, or angina. Rhoden, et al. Risks of Testosterone-Replacement Therapy and Recommendations for Monitoring N Engl J Med 2004; 350:482-492

29. Risks of Testosterone- Replacement Therapy 2. Lipid Profiles: Available data inconsistent (supraphysiologic doses appear to lower HDL). Some variability may be explained by dosage. Present data taken together suggest that testosterone replacement therapy within the physiologic range is not associated with worsening of the lipid profile. Rhoden, et al. Risks of Testosterone-Replacement Therapy and Recommendations for Monitoring N Engl J Med 2004; 350:482-492

30. Risks of Testosterone- Replacement Therapy 3. Polycythemia: Higher testosterone levels act as a stimulus for erythropoiesis. Injections appear to be associated with a greater risk than topical preparations. No testosterone-associated thromboembolic events have been reported to date.

31. Risks of Testosterone- Replacement Therapy 4. BPH: Prostate volume DOES increase significantly during testosterone-replacement therapy (determined by ultrasonography) mainly during the first 6 months. Poor correlation between prostate volume and urinary sxs. Multiple studies fail to demonstrate exacerbation of voiding sxs attributed to BPH during testosterone supplementation.

32. Risks of Testosterone- Replacement Therapy 5. Prostate Cancer: Prospective studies have demonstrated a low frequency of prostate cancer in association with testosterone- replacement rx. Occult prostate cancer in men with low testosterone levels appears to be substantial with higher grade prostate cancers. No compelling evidence to suggest men with higher testosterone levels are at a greater risk or that treating men who have hypogonadism with exogenous androgens increases this risk. Rhoden, et al. Risks of Testosterone-Replacement Therapy and Recommendations for Monitoring N Engl J Med 2004; 350:482-492

33. *Prostate cancer becomes more prevalent at the time of a man’s life when testosterone levels decline.

34. Risks of Testosterone- Replacement Therapy 6. PSA: Studies have inconsistently shown a rise in PSA in testosterone treated patients (0.3-0.4ng/ml) A substantial rise in PSA should arouse suspicion that a prostate cancer has developed.

35. Risks of Testosterone- Replacement Therapy 7. Hepatic Effects: Oral preparations of testosterone reported to lead to hepatotoxic effects and neoplasia, including benign and malignant tumors. IM injections and topical preparations of testosterone do not appear to be associated with hepatic dysfunction and routine monitoring of LFTs is unnecessary for men on these forms of replacement rx.

36. Risks of Testosterone- Replacement Therapy 8. Sleep Apnea: Testosterone-replacement therapy has been associated with the exacerbation of sleep apnea or with the development of sleep apnea (Seen in men treated with higher doses of parenteral testosterone and have other risk factors for sleep apnea). Probably by central mechanisms rather than by anatomical changes in the airway.

37. Miscellaneous Effects of Testosterone Breast tenderness and swelling Testicular size and consistency diminish Fertility is diminished Skin reactions with topicals Pain, bruising, soreness, furuncles with testosterone injections Fluid retention Acne, oily skin No data to suggest acceleration of male-pattern baldness.

38. Evaluation of the Possible Hypogonadal Male Physical exam: focus on whether or not sexual development is consistent with the patient’s age. Testicular size: 4-7cm in length. Normal musculature Dense pubic hair and in a diamond pattern. Beard should be full and dense Chest and other body hair should be present.

39. Laboratory Tests Serum Testosterone Measurement: Am total serum testosterone level Check free testosterone level in obese males and older males.(changes in SHBG) Repeat measurement if low or borderline level of testosterone

40. Low Testosterone Level Measure FSH and LH Prolactin level TSH MRI of Pituitary if FSH/LH low or not elevated?

41. Who To Treat With Testosterone- Replacement Therapy? Testosterone should be given ONLY to a male who is hypogonadal as evidenced by a low testosterone level. There is insufficient evidence that testosterone benefits elderly males without clearly abnormally low testosterone levels. Liverman. Testosterone and aging:Washingon DC:National Academies Press.

42. Baseline Exam/Tests Before Beginning Treatment With Testosterone Voiding history History of sleep apnea Perform DRE Baseline PSA and HCT/hemoglobin GU referral if PSA over 4.0 or abnormal prostate exam

43. Testosterone Preparations 1.Testosterone Esters: injectable testosterone 2.Transdermal: Nonscrotal patch Testosterone Gel Ointment Solution 3. Buccal tablet 4. Pellet (Testopel Implant)

44. Testosterone Esters Testosterone Esters: Injectable testosterone Testosterone enanthate and cypionate used for years in treatment of testosterone deficiency. Begin with 200mg IM every 2 weeks. Can change to 100mg every week if fluctuations in libido, mood, energy.

45. Testosterone Esters: Injectable testosterone Measure testosterone midway between injections and value should be mid-normal (600-700ng/ml) Reduce dose if higher values obtained. Disadvantage is fluctuations in mood, energy and libido in many patients

46. Nonscrotal Patch One body patch is available (Androderm) Worn on arm, torso, or thigh Start with 4mg patch Can check serum testosterone level at any time

47. Testosterone Gel Apply once per day Takes a month to reach normal levels and remain steady throughout 24 hours. Can check serum level at any time of day

48. Buccal Tablet Approved by FDA June, 2003 (Striant) Applied and adheres to a depression in the gum above the upper incisors and releases testosterone across the buccal mucosa

49. COST $$$$ Testosterone cypionate inj 1ml (200mg) $10.14 ($20.28/month) Testosterone 2 mg patch (1) $7.06 4mg patch (1) $14.11 ($211.18/month and $423.30/month)

50. Cost $$$$ Testosterone gel 1% 1.25GM/ACT (75GM) $212.62/month Testosterone gel 1.62% 20.25mg/ACT(75GM) $412.40/month Buccal testosterone 30mg (60) $517.50/month.

51. Follow-up of The Testosterone- Replaced Male Follow-up visit in 2-3 months for efficacy evaluation Assess urinary sxs/sleep apnea Perform DRE at ~3 months and q year thereafter Testosterone level at 2-3 months PSA at 3 months and q year thereafter HCT at 3 months and than yearly

52. WHAT’S NEW? “Gonadal Steroids and Body Composition, Strength, and Sexual Function in Men” NEJM 369;11, September 12, 2013

53. Methods 198 healthy men 20-50 years of age given goserlin to suppress endogenous testosterone and estradiol. Randomly assigned to receive placebo gel, or testosterone gel in different doses daily for 16 weeks. Another 202 healthy men received goserline, placebo gel or testosterone gel and anastrozle to suppress conversion of testosterone to estradiol. Primary outcomes were changes in percentage of body fat and in lean mass. Thigh muscle area and strength and sexual function also assessed along with subcutaneous and intraabdominal- fat areas.

54. Results % of body fat increased in groups receiving placebo or low dose of testosterone daily without anastrozole. Lean body mass and thigh-muscle area decreased in men receiving placebo and in those receiving low dose testosterone daily without ansatarozole. Leg press strength fell only with placebo administration. In general, sexual desire declined as the testosterone dose was decreased.

55. Conclusions The amt. of testosterone required to maintain lean mass, fat mass, strength, and sexual function varied widely in men. Androgen deficiency accounted for decreases in lean mass, muscle size, and strength. Estrogen deficiency primarily accounted for increases in body fat. Both testosterone deficiency and estrogen deficiency contributed to the decline in sexual function.

56. Summary: Endocrine Society Clinical Practice Guidelines for testosterone replacement therapy. Diagnosis of androgen deficiency only in men with consistent symptoms and signs with unequivocally low serum testosterone levels. Measure morning total testosterone. Confirm with repeat total testosterone and free or bioavailable testosterone using accurate assays

57. Guidelines continued Do not start testosterone therapy in patients with breast or prostate cancer, palpable prostate nodule or induration or PSA >3 without urologic evaluation. Severe LUTS HCT >50% Untreated OSA Severe CHF

58. CASE I AND II REVIEW