Late Onset Hypogonadism

1. Late Onset Hypogonadism Selvalingam.S Consultant Urologist

2. Historical Facts

3. First scietific documentationof declining vitality and sexual functions and its relation to male hormones is from: Eminent French physiologist and neurologist Brown-Séquard (1889) who injected himself with aqueous extracts from dogs’ testis and felt rejuvenated [1]. Gooren LJ. The age-related decline of androgen levels in men: clinically signif- icant. Br J Urol 1996;78:763–8.

4. 1944, Heller and Myers identified symptoms of what they also labeled the “male climacteric” : loss of libido and potency, nervousness, depression, impaired memory, the inability to concentrate, fatigue, insomnia, hot flushes, and sweating.

5. Meanwhile terms like ‘male menopause’ or ‘andropause’ or in the popular press ‘penopause’ became en vogue. Especially, andropause, meaning ‘the end of being a man’, became widely used.

6. In 1994 at the andrology workshop of the Austrian Urology Society, the term ‘partial androgen deficiency of the aging male’ with its acronym PADAM was introduced. Subsequently the term ‘late-onset-hypogonadism’ found its way into the literature,

7. Factors contributing to LOH- NOT the same as menopause

8. Diminished stimulation of the pituitary to produce the stimulatory hormone of the peripheral endocrine gland (Hypothalamic-Pituitary-Testis Axis) There are also testicular factors contributing to the decline of T production with aging The metabolic syndrome and its associated insulin resistance lower serum T

9. Several clinical studies confirm the inverse relationship between visceral obesity and depressed serum testosterone. In one study of elderly men with serum T levels ≤12.1 nmol/L: -71% were obese and -96% had an elevated waist circumference Saad F, Haider A, Doros G, Traish A. Long-term treatment of hypogonadal men with testosterone produces substantial and sustained weight loss. Obesity (Sil- ver Spring) 2013;21:1975–81.

10. Low serum T induces accumulation of visceral fat and its sequelae such as insulin resistance and dyslipidemia . In epidemiological studies serum T has a predictive value for the development of the metabolic syndrome and diabetes mellitus type 2 . Saad F, Aversa A, Isidori AM, Gooren LJ. Testosterone as potential effective ther- apy in treatment of obesity in men with testosterone deficiency: a review. Curr Diabetes Rev 2012;8:131–43. Camacho EM, Huhtaniemi IT, O’Neill TW, et al. Age-associated changes in hypothalamic–pituitary–testicular function in middle-aged and older men are modified by weight change and lifestyle factors: longitudinal results from the European Male Ageing Study. Eur J Endocrinol 2013;168:445–55.

14. Definition Of Late Onset Hypogonadism (LOH) Three sexual symptoms (decreased morning erection and sexual thoughts and erectile dysfunction) with a low T level, of less than 11 nmol/L and free T < 225 pmol/L be required in order to diagnose LOH. EMAS

15. Although symptoms may vary from person to person, common symptoms of men going through LOH include: 1. low sex drive 2. difficulties getting erections or erections that are not as strong as usual 3. lack of energy 4. depression 5. irritability and mood swings 6. loss of strength or muscle mass 7. increased body fat 8. hot flashes

16. Essential in diagnosis: • A comprehensive medical, psycho-social and life-style history, • History on acute, chronic and inter-current illness • Physical examination and • Laboratory testing.

17. The Endocrine Society recommends the evaluation of total T in subjects with : Erectile dysfunction, Hypothalamic/pituitary diseases Subjects taking medications interfering with T release or action, such as glucocorticoids and opiates. The screening for low T is also recommended in : Type 2 diabetes mellitus (T2DM), Metabolic syndrome (MetS), HIV and Chronic obstructive lung disease (COPD).

18. Interventions such as hormone therapies may favorably influence some of the pathological conditions in aging men by preventing the preventable and delaying the inevitable.

19. Benefits of Testosterone Replacement Therapy

20. Weight Reduction and reduction in waist circumferance

24. Reduction in Blood Pressure

26. Reduction in lipids and glucose

30. Benefit to the Bones

31. The fracture-related morbidity and mortality are often greater than in women due to the frailty of men [20]. Studies demonstrate that normal serum T is required to maintain bone mineral density at various stages of life [21]. Kannegaard PN, van der Mark S, Eiken P, Abrahamsen B. Excess mortality in men compared with women following a hip fracture. National analysis of comedi- cations, comorbidity and survival. Age Ageing 2010;39:203–9. Fink HA, Ewing SK, Ensrud KE, et al. Association of testosterone and estradiol deficiency with osteoporosis and rapid bone loss in older men. J Clin Endocrinol Metab 2006;91:3908–15.

33. Benefit to Urinary Symptoms and ED

34. The relationship between LUTS and erectile dysfunction is the role that nitric oxide/cyclic GMP signaling plays in both erectile dysfunction and LUTS/BPH. Both LUTS and ED are related to the presence of the metabolic syndrome and normalization of serum T improves LUTS . Park YW, Kim SB, Kwon H, et al. The relationship between lower urinary tract symptoms/benign prostatic hyperplasia and the number of components of metabolic syndrome. Urology 2013;82:674–9. Yassin DJ, El Douaihy Y, Yassin AA, Kashanian J, Shabsigh R, Hammerer PG. Lower urinary tract symptoms improve with testosterone replacement therapy in men with late-onset hypogonadism: 5-year prospective, observational and longitudinal registry study. World J Urol 2013 [Epub ahead of print].

36. Safety of Testosterone Replacement

37. T Replacement and Prostate Cancer A meta-analysis of T treatment in older men was not associated with a significantly higher risk of detection of prostate cancer in comparison to placebo. T appears not to be the main factor in the development or progression of prostate cancer in men . Morgentaler A, Lipshultz LI, Bennett R, Sweeney M, Avila Jr D, Khera M. Testosterone therapy in men with untreated prostate cancer. J Urol 2011;185: 1256–60. Atan A, Tuncel A, Yesil S, Balbay D. Serum testosterone level, testosterone replacement treatment, and prostate cancer. Adv Urol 2013;2013:275945.

39. T replacement and BPH Voiding symptoms due to benign prostatic hyperplasia did not exacerbate following T treatment in men . Calof OM, Singh AB, Lee ML, et al. Adverse events associated with testosterone replacement in middle-aged and older men: a meta-analysis of randomized, placebo-controlled trials. J Gerontol A Biol Sci Med Sci 2005;60:1451–7.

40. Testosterone Replacement and CV disease

41. Over the last years there has also been a number of publications about the potentially deleterious effects of testosterone administration in elderly men with frailty and/or immobility . BasariaS,CovielloAD,TravisonTG,etal.Adverseeventsassociatedwithtestos- terone administration. N Engl J Med 2010;363:109–22. FinkleWD,GreenlandS,RidgewayGK,etal.Increasedriskofnon-fatalmyocar- dial infarction following testosterone therapy prescription in men. PloS One 2014;9:e85805. Vigen R, O’Donnell CI, Baron AE, et al. Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. JAMA 2013;310:1829–36.

42. Androgen therapy was regarded a risk for developing CVD. Several studies have examined the relationship of androgens with CVD and the conclusion was that T cannot be regarded as a culprit in the etiology of CVD Traish AM, Saad F, Feeley RJ, Guay A. The dark side of testosterone deficiency: III. Cardiovascular disease. J Androl 2009;30:477–94. Traish AM, Kypreos KE. Testosterone and cardiovascular disease: an old idea with modern clinical implications. Atherosclerosis 2011;214:244–8.

43. Methods of Testosterone Replacement Therapy (TRT)

44. Topical Treatment

48. Oral Preparation

49. Injectable

50. Take Home Message