2. http://www.isitlowt.com

3. What is [Low-T]?

6. Definition of Male Hypogonadism Hypogonadism in men is a clinical syndrome that results from failure of the testis to produce physiological levels of testosterone (androgen deficiency) and a normal number of spermatozoa due to disruption of one or more levels of the hypothalamic-pituitary testicular axis Endocrine Society clinical practice guideline Wang C et al. Aging Male 2009;12(1):5– 12

7. Clinical Diagnosis – H&P Symptoms (non-specific) – Fatigue, decreased libido, erectile dysfunction – Androgen Deficiency in Aging Males (ADAM) test

8. http://www.isitlowt.com

10. Screening test for depression?

11. Clinical Diagnosis – H&P Symptoms (non-specific) – Fatigue, decreased libido, erectile dysfunction – Androgen Deficiency in Aging Males (ADAM) test Associated disease states e.g. obesity, COPD, metabolic syndrome, diabetes, etc. – Is low-T the cause of these diseases? – Is it a complication of these diseases? – Is it a co-morbidity?

12. Clinical Diagnosis – H&P Symptoms (non-specific) – Fatigue, decreased libido, erectile dysfunction – Androgen Deficiency in Aging Males (ADAM) test Associated disease states e.g. obesity, COPD, metabolic syndrome, diabetes, etc. – Is low-T the cause of these diseases? – Is it a complication of these diseases? – Is it a co-morbidity? Signs – Mostly associated with congenital or developmental hypogonadism (e.g. Klinefelter’s, undescended testes)

14. Definition of Male Hypogonadism Hypogonadism in men is a clinical syndrome that results from failure of the testis to produce physiological levels of testosterone (androgen deficiency) and a normal number of spermatozoa due to disruption of one or more levels of the hypothalamic-pituitary testicular axis Endocrine Society clinical practice guideline Wang C et al. Aging Male 2009;12(1):5– 12

15. Lab Diagnosis of Hypogonadism Total testosterone <300 ng/dl Based upon lower limit of total testosterone in young men (usually quoted normal range of 300-1000 ng/dl) No generally accepted lower limit of normal (lower limit is 220 ng/dl at the Cleveland Clinic) Does not necessarily reflect free testosterone levels Should 70-yr old men be judged by norms for 30-yr olds? 15% of healthy young men will have a testosterone level below the normal range in any 24 hour period Not necessarily indicative of “physiological levels of testosterone”

17. Hypogonadism defined as Total Testosterone <300ng/dl

19. Definition of Male Hypogonadism Hypogonadism in men is a clinical syndrome that results from failure of the testis to produce physiological levels of testosterone (androgen deficiency) and a normal number of spermatozoa due to disruption of one or more levels of the hypothalamic-pituitary testicular axis Endocrine Society clinical practice guideline Wang C et al. Aging Male 2009;12(1):5– 12

20. Low-T ≠ T-Deficiency Low Testosterone levels do NOT necessarily indicate hypogonadism or testosterone deficiency – testosterone levels can be low in normal, healthy young men with normal sperm counts – lots of false positives with low serum testosterone levels alone Low sperm counts are necessary for the diagnosis of hypogonadism, but seldom done Low-T + Oligospermia = Hypogonadism

21. Work-up of Hypogonadism LH/FSH  primary vs. secondary If LH/FSH are inappropriately low, need to get – TSH – am cortisol level – prolactin level to rule out S.O.L. – Consider MRI Diagnosis of Low-T is made without ANY blood work in 20% of cases Diagnosis of Low-T generally made without sperm counts or LH/FSH levels

22. Primary Hypogonadism Testicular etiology Causes: Undescended testes Klinefleter’s syndrome Hemochromatosis Mumps orchitis Injury to testes (e.g. cancer therapy) Classification of Hypogonadism

23. Secondary Hypogonadism Extra-testicular etiology Causes: Hypothalamic disorders (e.g. Kallmann syndrome) Pituitary disorders (e.g. tumor, surgery, radiation) Inflammatory disorders (e.g. TB, sarcoidosis) Medications (especially opioids) Obesity HIV

24. http://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/endocrinology/male-hypogonadism/ Testosterone Declines Age

25. Late-Onset Male Hypogonadism “Late onset hypogonadism (LOH, also referred to as age-associated testosterone deficiency, TDS) is a clinical and biochemical syndrome associated with advancing age and characterized by symptoms and a deficiency in serum testosterone levels (below the young healthy male reference range)” ISA, ISSAM, EAU, EAA and ASA recommendations (2009) Bhasin S et al. J Clin Endocrinol Metab 2010;95(6):2536–2559

26. Late-Onset Hypogonadism (LOH) Alternate Terminology Testosterone-Deficiency Syndrome (TDS) Age-Related Testosterone Deficiency Andropause Androgen Deficiency of the Aging Male (ADAM) Partial Androgen Deficiency of the Aging Male (PADAM)

27. LOH = Low-T (+ oligospermia)

28. OK, Testosterone declines with age … But is LOH a deficiency syndrome? or a degenerative syndrome?

29. DEFICIENCYDEGENERATIVE PathologicalNormal in the context of Aging? Completely ReversibleNot Readily Reversed No Side Effects if in Physiological Range Side Effects Possible (No Therapeutic Target Range)

30. If Low-T were a deficiency … Artwork from: http://www.sci-news.com/medicine/science-low-testosterone-heart-problems-01418.html

31. then the syndrome should be completely reversible Artwork from: http://www.sci-news.com/medicine/science-low-testosterone-heart-problems-01418.html

32. If Low-T were degenerative … Artwork from: http://www.sci-news.com/medicine/science-low-testosterone-heart-problems-01418.html

33. then the syndrome is not so reversible Artwork from: http://www.sci-news.com/medicine/science-low-testosterone-heart-problems-01418.html

34. Reversing Effects of Low-T ? Maintains bone density Supports collagen Face/body hair Male-pattern baldness Aggressiveness Promotes prostate growth Red blood cell production Sex drive Erectile function Well-being & energy Builds muscle mass Sperm production Promotes heart health Anti-obesity/diabetes Prevents Alzheimer’s Effects Attributed to Testosterone

35. Reversing Effects of Low-T ? Maintains bone density Supports collagen Face/body hair Male-pattern baldness Aggressiveness Promotes prostate growth Red blood cell production Sex drive Erectile function Well-being & energy Builds muscle mass Sperm production Promotes heart health Anti-obesity/diabetes Prevents Alzheimer’s Effects Attributed to Testosterone

36. Risks of Treating Low T Possible adverse effects of treatment BPH / elevation of PSA Acceleration of prostate CA / breast CA Mortality, MI and stroke* DVT Worsening of OSA Polycythemia No physiological target range *Vigen et al. JAMA 2013 Nov 6;310(17):1829-36; Basaria et al. NEJM 2010 Jul 8;363(2):109-22

37. Originator of “Low-T” Dr. Abraham Morgentaler claims to have coined the term “years ago” – Founder of Men’s Health Boston – Author of “Testosterone for Life” – associate clinical professor of urology at Harvard Medical School – On Speaker Bureaus for Watson, Abbott (Abbvie), Auxillium, Endo (not up to date) – Industry funded research/investigator for GSK (not up to date) Claims testosterone does NOT cause prostate cancer

38. Is it a deficiency syndrome or a triumph of marketing?

40. Excerpt from Abstract: In the absence of any new indications, off-label testosterone prescribing has increased in most countries in 2000–2011, especially over the last half of the period … … By eliminating the fundamental distinction between pathological and functional androgen deficiency, these guidelines tacitly promote increased testosterone prescribing, bypassing the requirement for high-quality clinical evidence of safety and efficacy and creating dramatic increases in prescription of testosterone products. Handelsman DJ. Med J Aust. 2013 Oct 21;199(8):548-51

41. Low “T” as in “Template” How to Sell Disease Schwartz and Woloshin, JAMA Intern Med. 2013;173(15):1460-1462 Three strategies: 1.Lower the bar – broaden the criteria for definition to include more people 2.Raise the stakes – “It is one thing to tell men that Low T can make them grumpy; it is another to say that it can kill them.” 3.Spin the evidence – list symptoms/conditions associated with low endogenous testosterone; implication problems reversed with restoration exogenous testosterone

42. For baby-boomers, it’s all about SEX!

43. You know it’s really working when …

44. A man on TV is selling me a miracle cure that will keep me young forever. It’s called Androgel…for treating something called Low T, a pharmaceutical company–recognized condition affecting millions of men with low testosterone, previously known as getting older. The Colbert Report, December 2012

45. Direct to Consumer Advertising from Abbvie (formally Abbott) (makers of Androgel)

47. Are our memories really that short? Remember What?

48. Women are Clearly Smarter than Men Hello …?

49. Remember Premarin? Women are Clearly Smarter than Men

50. Published in 1964 Dr. Robert Wilson “… menopause is a Hormone deficiency and totally preventable” Today, it would be called: [Low-E]

54. Purported Benefits of Premarin Prevents hot flushes Prevents osteoporosis Prevents vaginal atrophy Keeps skin young by maintaining collagen Reduce risks of heart attacks & strokes Prevents Alzheimer’s Prevents age-related macular degeneration Reduce colon cancer risk Help prevent diabetes, Parkinson’s, tooth loss, etc. http://www.hotzehwc.com/en-US/Resource-Center/Articles/Broken-Promises--The-History-of-HRT.aspx

55. Data Actually Showed … 1997: meta-analysis of 51 epidemiological studies  increased risk of breast cancer 1998: Heart Estrogen/Progestin Replacement Study (HERS)  no heart benefit, higher rates of cardiovascular disease 2002: Women’s Health Initiative (WHI)  halted 3 years early due to risks of breast cancer and DVT/PE 2003: further analysis of WHI showed increased risks of breast CA and cardiovascular events 2013: estrogen might not increase cardiovascular toxicity in early menopause

56. Estrogen safe in early menopause? - Comparing Menopause & Andropause Diagnosis of menopause is very specific, but diagnosis of LOH is plagued by false positives Menopause = Low-E Low-T ≠ Andropause Menopause is abrupt; andropause is gradual what is early andropause? Ok to treat flushing, osteoporosis, not as a hormone to restore youth SAFETY OF TESTOSTERONE THERAPY CANNOT BE INFERED FROM WHI

57. Bottom Line: Testosterone replacement therapy is probably not warranted at this time and should not be recommended until and unless long-term studies demonstrate benefits outweigh risks of therapy

59. MEDICALIZATION $ $ $ $ $ $ $

60. Medicalization is a social process through which a previously normal human condition (behavioral, physiological or emotional) becomes a medical problem in need of treatment under the jurisdiction of medical professionals.

62. Examples of Medicalization Less Controversial Low-T Menopause ED Mammary hypoplasia Micrognathia Overbite/underbite Acne Circumcision More Controversial Nutritional deficiency Precocious puberty Psychiatric diagnoses (e.g. social anxiety, ADHD, bipolar disorder) Hyperlipidemia Pain Abnormal test results (e.g. Pap smears, PSA)

63. Did I lose anyone? QUESTIONS? Email:sfeng@johnsonmemorial.org