Andrapause a deep look pathophysiology and clinical management.pptx

the presentation discusses the magnitude of the problem,
Evidence based strategies for management .
clinical pearls for 1ry health care providers

1. Male Andropause : A Myth or Reality Mesbah Sayed Kamel , MD President Diabetes in Asia Study Group (DASG) Vice-President Upper Egypt Diabetes Association (UEDA)

2. Disclosure

3. AGENDA Definition &Synonyms. Magnitude of the problem and Role of testosterone. Pathophysiology. Presentations. Diagnosis. Management. Take-Home messages.

4. AGENDA Definition &Synonyms. Magnitude of the problem and Role of testosterone. Pathophysiology. Presentations. Diagnosis. Management. Take-Home messages.

5. Definition In Greek Andras ” means human male and “pause” means a cessation; so literally “ andropause ” is defined as  a syndrome associated with a decrease in sexual satisfaction , hypogonadism , physical decline and psychological changes with low levels of testosterone in older man . Is also… called Late Onset Hypogonadism (LOH) , which is caused by functional (and hence potentially reversible) suppression of the HPT axis due to accumulation of age-related comorbidities, especially obesity These changes adversely affecting multiple organs resulting in significant alterations in quality of life. Am J Ther . 2006 Mar-Apr;13(2):145-60. Management of the cardinal features of andropause . Mooradian AD, Korenman SG. AFP Volume 43, No.5, May 2014 Pages 277-282Assessment and management of male androgen disorders: an update

6. Synonyms PADAM:Partial Androgen Deficiency in Aging Male. ADAM: Androgen Deficiency in Aging Male. Male Climacteric. Viropause. Relative Hypogonadism. Hypoandrogenemia. Manopause. Late-Onset Hypogonadism.

7. AGENDA Definition &Synonyms. Magnitude of the problem and Role of testosterone. Pathophysiology. Presentations. Diagnosis. Management. Take-Home messages.

8. Prevalence differs according to studies methodology. Considering the hypogonadal symptoms 12-25% of men over 40Ys reporting one or more symptoms of hypogonadism and it increases substantially with age . Considering Testosterone level 40% of American men over age 40 have low testosterone levels . European Male Aging Study (EMAS) data reported prevalence of 2.1% as assessed by low testosterone and presence of three sexual symptoms of these only 5–35% of hypogonadal males actually receive treatment for their condition. Mulligan T, Frick MF, Zuraw QC, Stemhagen A, McWhirterC . Prevalence of hypogonadism in males aged at least 45 years: the HIM study. Int J Clin Pract 2006; 60:762-9. Time for international action on treating testosterone deficiency syndrome. Carruthers M. Aging Male. 2009 Mar;12(1):21-8. Indian J Endocrinol Metab .  2013 Dec; 17( Suppl 3): S621–S629

9. Androgen Decline… Why Worry? Low serum testosterone is associated with decreased muscle mass and insulin resistance leading to increased male mortality. In an observational cohort of men with low testosterone levels, testosterone treatment was associated with decreased mortality compared with no testosterone treatment Arch Intern Med. 2006 Aug 14-28;166(15):1660-5. Low serum testosterone and mortality in male veterans. Shores MM1, Matsumoto AM, Sloan KL, Kivlahan DR. J Clin Endocrinol Metab . 2012 Jun;97(6):2050-8. Testosterone treatment and mortality in men with low testosterone levels. Shores MM, Smith NL, Forsberg CW, Anawalt BD, Matsumoto AM.

10. Maggio M & Basaria S. Int J Impot Res. 2009;21(4):261–4. Low androgen levels are associated with many cardiovascular risk factors Cardiovascular disease Insulin resistance Vascular stiffness Metabolic syndrome Atherosclerosis Hypertension Dyslipidemia Inflammation Diabetes Male hypogonadism Mortality

11. Role of Testosterone

12. AGENDA Definition &Synonyms. Magnitude of the problem and Role of testosterone. Pathophysiology. Presentations. Diagnosis. Management. Take-Home messages.

13. Reported testosterone production rates ranging from 3.0–7.0 mg/day in healthy men Kley HK, Niederau C, Stremmel W, Lax R, Strohmeyer G, Krüskemper HL. 1985 Conversion of androgens to estrogens in idiopathic hemochromatosis: comparison with alcoholic liver cirrhosis. J Clin Endocrinol Metab . 61:1–6. Meikle AW, Stringham JD, Bishop DT, West DW. 1988 Quantitating genetic and nongenetic factors influencing androgen production and clearance rates in men. J Clin Endocrinol Metab . 67:104–109

14. Andropause in men typically occurs between the ages of 40 and 60. But men as young as 30 may begin to experience andropause symptoms.

15. Rhoden EL & Morgentaler A. N Engl J Med. 2004;350(5):482–92. Hypogonadism: testosterone levels naturally decline with age Men with hypogonadism (%) Age (years)

16. HYPOTHALAMUS PITUITARY + GNRH + FSH + LH - TESTOSTERONE TESTES HPT Axis Feedback Mechanism

17. LH, luteinizing hormone; LHRH, luteinizing hormone-releasing hormone; SHBG, sex hormone-binding globulin; TDS, testosterone deficiency syndrome Nieschlag E et al. Andrology: Male reproductive health and dysfunction, 3rd edition, Springer, 2010. Hypogonadism/TDS: mechanism of down-regulation of testosterone levels Increased sensitivity to testosterone Testosterone SHBG Testosterone SHBG Reduced LHRH Reduced LH Pituitary gland Hypothalamus Testis Testicular and hypophyseal -hypothalamic insufficiency prevents an increase in testosterone secretion from the testis Serum SHBG levels increase with age, decreasing the amount of bioactive free testosterone

18. HYPOTHALAMUS PITUITARY + GNRH + FSH + LH - TESTOSTERONE TESTES HPT Axis Elevated Estrogen GnRH is secreted from the hypothalamus LH secretion from the pituitary is stimulated by GnRH LH stimulates the secretion of testosterone from the testes

19. 1-Decreased GnRH pulse amplitude 2-Circadian disruption 3-Increased sensitivity to negative feedback 1-Decreased Lyedig cell number (age-related) 2-Decreased Lyedig cell function Increased aromatase activity converting testosterone to estrogen Reduction in the amount of free testosterone due to protein binding with sex hormone binding globulin (SHBG)

20. Andropause:Basic underlying process is Age –Related Decreased Testosterone and Increased Estradiol

21. SHBG, sex hormone-binding globulin Comhaire FH. Eur Urol. 2000;38(6):655–62. Age-related changes in s erum testosterone and SHBG concentrations Serum concentrations Age (years)

22. SHBG Change With Weight Loss and Excercise EMAS Int J Androl . 2009 Lee DM, et al.

23. Things That Lower Testosterone In Men Certain drugs: Statins, beta blockers, H2 antagonist, benzodiazepines, antifungals, opioids, corticosteroids, SSRI’s , Chemotherapy, NSAIDs (ibuprofen), Tylenol, ASA Infections: Mumps Alcohol, stress, obesity High glycemic foods: Sugar , flour, processed carbs

24. Studies have shown that a  1-week reduction in sleep   (to an average of 5 hours per night) lowered testosterone level by 10-15%. 

25. The daily pattern of male testosterone production is attenuated with age LH, luteinizing hormone Bremner WJ et al. J Clin Endocrinol Metab . 1983;56(6):1278–81; O’Donnell L et al. Endocrinology of the male reproductive system and spermatogenesis. Endotext . South Dartmouth (MA); 2017. Testosterone concentration (ng/mL) 08:00 12:00 16:00 20:00 24:00 08:00 04:00 Time (h) Younger men Older men The testes’ capacity to secrete testosterone declines in ageing men, because of a reduced ability to respond to LH pulses

26. Why does estrogen go up? Androgen to estrogen conversion(Increased Aromatase activity) Lifestyle induced (Stress, Lack of Exercise, Poor Diet leading to Insulin Resistance,sleep deprivation and circadian disruption). Estradiol levels correlate significantly to body fat mass and more specifically to subcutaneous abdominal fat.(Metabolic Syndrome ). Relative hypogonadism was strongly associated with the prevalence of metabolic syndrome in Japanese adult men who were newly diagnosed to have IGT or type 2 diabetes Metabolic syndrome group had a significantly lower Test./estradiol and SHBG level (p < 0.01). Metab Syndr Relat Disord . 2004 Spring;2(1):39-48. Association between Relative Hypogonadism and Metabolic Syndrome in Newly Diagnosed Adult Male Patients with Impaired Glucose Tolerance or Type 2 Diabetes Mellitus. Zou B1, Sasaki H, Kumagai S. Endocr Rev. 2004 Jun;25(3):374-88.

27. AGENDA Definition &Synonyms. Magnitude of the problem and Role of testosterone. Pathophysiology. Presentations. Diagnosis. Management. Take-Home messages.

28. Presentations: "Mayo Clinic." Testosterone : Key to male vitality? . Mayo Foundation for Medical Education and Research, 10 Apr 2012 . Combined effects of sex hormone-binding globulin and sex hormones with high estradion and low testosterone are implicated in risk of incident type 2 diabetes.( J Diabetes. 2015 Jun 29. doi : 10.1111/1753-0407. Hu J1, Zhang A, Yang S, Wang Y, Goswami R, Zhou H, Zhang Y, Wang Z, Li R, Cheng Q, Zhen Q, Li Q.)

29. AGENDA Definition &Synonyms. Magnitude of the problem and Role of testosterone. Pathophysiology. Presentations. Diagnosis . Management. Take-Home messages.

30. Diagnosis Andropause diagnosis requires the presence of both low testosterone levels and clinical symptoms. The use of free testosterone as a more specific marker in cases where Sex Hormone Binding Globulin (SHBG) alterations are suspected has also been a matter of discussion.  Results from EMAS proposed the minimum criteria for the diagnosis of LOH in aging men: presence of three sexual symptoms (decreased libido, morning erections, and erectile dysfunction) combined with a total testosterone level of less than 11 nmol /l and a free testosterone level of less than 220 pmol /l . Questionnaires such as Aging Male Symptom (AMS) Score and ADAM are not recommended for the diagnosis of hypogonadism because of low specificity (30 and 39%, respectively). Indian J Endocrinol Metab .  2013 Dec; 17( Suppl 3): S621–S629

31. Questionnaires for hypogonadism screening and outcome measurement Several patient- and clinician-reported instruments exist for hypogonadism screening and outcome measurement Androgen Deficiency in the Aging Male Aging Male’s Symptoms scale Massachusetts Male Aging Study These questionnaires may assist: Assessment of symptoms prior to starting TTh Monitoring of clinical response to TTh during follow-up Patient adherence to TTh Clinical documentation Bhasin S et al. J Clin Endocrinol Metab . 2010;95(6):2536–59; Dean JD et al. J Sex Med. 2015;12(8):1660–86; Dohle GR et al. EAU guidelines on male hypogonadism. 2017. http://uroweb.org/guideline/male-hypogonadism/; Lunenfeld B et al. Aging Male. 2015;18(1):5–15. ADAM AMS MMAS

32. Testosterone level cut-offs There is no universally accepted lower limit of ‘normal’ for testosterone level, and it is unclear whether geographically different thresholds depend on ethnic differences or the clinician’s perception 1,2 However, there is general agreement that: 1–6 *Consider TTh in individual cases, based on total T concentrations/symptoms and low calculated free T concentrations 6 SHBG, sex hormone-binding globulin; T, testosterone; TDS, testosterone deficiency syndrome; TTh , testosterone therapy 1. Nieschlag E et al. J Androl . 2006;27(2):135–7. 2. Dean JD et al. J Sex Med. 2015;12(8):1660–86. 3. Dohle GR et al. EAU guidelines on male hypogonadism. 2017. http://uroweb.org/guideline/male-hypogonadism/ 4. Lunenfeld B et al. Aging Male. 2015;18(1):5–15. 5. Hackett G et al. Int J Clin Pract . 2017;71(3–4):e12901. 6. Traish AM et al. Am J Med. 2011;124(7):578–87. TDS unlikely Consider TTh * Total T <8 nmol /L (231 ng/ dL ) or Free T <180 pmol /L (5.2 ng/ dL ) TDS likely TTh indicated Total T 8–12 nmol /L (231–346 ng/ dL ) or Free T 180–225 pmol /L (5.2–6.5 ng/ dL ) TDS possible, consider TTh (if presence of bothersome symptoms and/or elevated SHBG) Total T >12 nmol /L (346 ng/ dL ) or Free T >225 pmol /L (6.5 ng/ dL )

33. 1 2 A B 3 B A 4 1ry HG 2ndry HG

34. Traish AM et al. Am J Med. 2011;124(7):578–87. Diagnostic evaluation of adult men with suspected hypogonadism Assess free T Assess total T Consider ≥1 of the following tests, depending on the clinical situation: Gonadotropins, free T Prolactin, estradiol Thyroid and adrenal axes Stimulation test of pituitary gland Karyotype, fertility status Testicular ultrasound MRI of pituitary gland/hypothalamus Possible co-operation with an andrologist or endocrinologist Clinical symptoms/signs of testosterone deficiency Presence of ≥1 components of the metabolic syndrome Erectile dysfunction Total T <8 nmol /L (<250 ng/ dL ) Total T 8–12 nmol /L (250–350 ng/ dL ) Total T >12 nmol /L (>350 ng/ dL ) Free T <270 pmol /L (<8 ng/ dL ) Proceed with trial of TTh (after exclusion of contraindications) Follow-up visit at 3 and 6–12 months thereafter: Efficacy of treatment? Hematocrit and PSA normal? Add PDE-5 inhibitor?

35. T firmly bound to SHBG 60% BIOAVAILABLE TESTOSTERONE = Albumin-bound T + Free T Free T T loosely bound to albumin 2% 38% Testosterone binding (T)

36. Recommendations on measuring testosterone levels Measure total testosterone between 07:00–11:00 1–4 Serum testosterone levels exhibit a circadian variation with peak values in the morning between 06:00–08:00 and a nadir between 18:00–20:00 2,3 Clinical symptoms of hypogonadism may be less clear in older individuals because of blunting of the diurnal variation of testosterone secretion and other age-related changes 2,3 If testosterone levels are below or at the lower limit of accepted normal adult male values [ e.g. total testosterone <12 nmol /L (346 ng/ dL )] , a second measurement of total and/or free testosterone, together with LH and prolactin (and SHBG, in obese and older men) should be performed 1–4 LH, luteinizing hormone; SHBG, sex hormone-binding globulin 1. Dean JD et al. J Sex Med. 2015;12(8):1660–86. 2. Bhasin S et al. J Clin Endocrinol Metab . 2010;95(6):2536–59. 3. Lunenfeld B et al. Aging Male. 2015;18(1):5–15. 4. Dohle GR et al. EAU guidelines on male hypogonadism. 2017. http://uroweb.org/guideline/male-hypogonadism/

37. Differential Diagnosis

38. AGENDA Definition &Synonyms. Magnitude of the problem and Role of testosterone. Pathophysiology. Presentations. Diagnosis . Management. Take-Home messages.

39. Andropause Is more than just hypogonadism! Treat the whole Patient – support the problem constellation

40. Approach Does every older male patient need testosterone therapy? With low testosterone does he have ED and/or osteoporosis? Are other comorbidities in need of treating first? Does he need lifestyle modification? Is insulin resistance the underlying metabolic malfunction? Is alcohol part of the problem? Is he maintaining his physical stamina?

41. Andropause Treatment Parameters Treat the patient, not the lab values As symptoms warrant, treat with those hormones where the levels are less than optimal or below range Start low and go slow Dosage adjustments as needed Scheduled follow-up re-evaluations

42. Endocrine Society Clinical Guidelines 2010 Offering testosterone therapy on an individualized basis to older men with low testosterone levels on more than one occasion and clinically significant symptoms of androgen deficiency, after explicit discussion of the uncertainty about the risks and benefits of testosterone therapy. Life style modifications essentialy based on increasing physical activity and weight loss are strongly recommended in hypogonadal subjects with obesity, type 2 diabetes and metabolic syndrome. Weight loss, however it is obtained results in significant reversal of obesity associated hypogonadism . Disagreement on serum testosterone levels below which testosterone therapy should be offered to older men with symptoms. Depending on the severity of clinical manifestations, some panelists favored treating symptomatic older men with a testosterone level below the lower limit of normal for healthy young men (280–300 ng /dl (9.7–10.4 nmol /l)); others favored a level below 200 ng /dl (6.9 nmol /l). 

43. Preparations of natural testosterone should be used for substitution therapy. Currently available intramuscular, transdermal, oral, and buccal preparations of testosterone are safe and effective. The treating physician should have sufficient knowledge and adequate understanding of the pharmacokinetics as well as of the advantages and drawbacks of each preparation. The selection of the preparation should be a joint decision of an informed patient and physician. Since the possible development of an adverse event during treatment (especially elevated hematocrit or prostate carcinoma) requires rapid discontinuation of testosterone substitution, so short-acting preparations may be preferred over long-acting depot preparations in the initial treatment of patients with LOH. Testosterone replacement therapy

44. Testosterone Forms IM common form Transdermal SL or Troche Pellets Rectal Oral

45. IM Testosterone 75mg to 100mg weekly is common Have seen 150 to 160mg weekly also Testosterone cypionate and enanthate often compounded together Combinations of testosterone cypionate with anastrozole

46. Transdermal Testosterone Commercial gel dosing of “1% is 50 mg of testosterone (4 pump actuations, two 25 mg packets, or one 50 mg packet), applied topically once daily in the morning to the shoulders and upper arms and/or abdomen area (preferably at the same time every day).”

47. Testosterone Use In Males Dosage: “Nat-ism” Transdermal cream or gel 10 to 15mg daily starting dosage Injection 20 to 30mg SQ - M,W,F 75 – 100mg IM weekly

48. Treatment Follow-up Re-test (3 months) Re-Evaluate symptoms Adjust dosage and or regimen Remember: Treat the patient not the lab value!

49. Contraindications to testosterone replacement Ca prostate NB - subclinical carcinoma (>50% of >70y olds) effects unknown Polycythaemia Sleep apnoea

50. The triple combination therapy of : Testosterone + HCG:HCG helps maintain testicular size and provides a natural boost to testosterone levels to boot. + An estrogen blocker(aromatase inhibitor ,usually Arimidex )  should be considered proper and healthy testosterone replacement therapy.

51. AGENDA Definition &Synonyms. Magnitude of the problem and Role of testosterone. Pathophysiology. Presentations. Diagnosis . Management. Take-Home messages.

52. Take Home Message Andropause is an underestimated male problem ,frequently un noticed. Early diagnosis and proper management are essential. Life style modifications especially weight reduction and Exercise are the corner stones in management. Testosterone therapy should be individualized and properly monitored .