Male Hypogonadism, LOH,


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Male Hypogonadism :etiology , pathophysiology , prevalence , diagnosis by R.Tavakkolnia MD, urologist

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Male Hypogonadism, LOH,

  2. 2. Hypothalamic-Pituitary-Testis Axis Inhibin B 2
  3. 3. Definition Hypogonadism in men is a clinical syndrome that results from failure of the testis to produce physiological levels of testosterone (androgen deficiency) and the normal number of spermatozoa due to disruption of one or more levels of the hypothalamic-pituitary-gonadal (HPG) axis. 3
  4. 4. Definition A decrease in either of the two major functions of the testes: – sperm production And / or – testosterone production 4
  5. 5. Primary Hypogonadism  GnRH T  LH / FSH T T  Sperm  E2  DHT  Inhibin B 5
  6. 6. DDx: Primary Hypogonadism1. Klinefelter Syndrome2. XX Male (Sex Reversal)3. Noonan Syndrome (Male Turner Syndrome)4. Myotonic Dystrophy5. Congenital Anorchia (Vanishing Testis Syndrome)6. Sertoli-Cell-Only Syndrome7. Acquired Germinal Cell Aplasia8. Orchitis9. Others : CRF, Cirrhosis, HIV, Drugs, XRT, 6
  7. 7. Primary HypogonadismKlinefelter Syndrome46 XXY, 46 XY/XXY, 48 XXXY1 in 500 menEunuchoid lower segment, Taller than Average,Gynecomastia , Gynecoid Features, Very Small Testis,Normal to Low Testosterone, FSH increase >LH,Modest Elevation of Estradiol,Severe Oligospermia to AzospermiaAssociated Conditions: COPD, Cancer of Breast, GermCell Tumors, Autoimmune Diseases, Diabetes Mellitus,Osteopenia, Mitral Valve Prolapse, Mental Slowness,Antisocial Behavior 7
  8. 8. Klinefelters syndrome 8
  9. 9. Primary HypogonadismXX Male (Sex Reversal)Translocation of the SRY gene, Shorter than Average, Normal Intelligence, Gynecomastia, Small Testis, AzospermiaNoonan Syndrome (Male Turner Syndrome)46 XY, Short Stature, Webbed Neck, Shield Chest, Small Testis, Impaired Spermatogenesis, May Have Low TestosteroneAssociated Conditions: Mental Retardation, Pulmonary Stenosis, Hypertrophic Cardiomyopathy, 9
  10. 10. Primary HypogonadismMyotonic DystrophyAutosomal Dominant Inability to Relax Striated Muscle, Frontal Balding, Ptosis , Cataracts , Atrophy of Facial Muscles , Distal Muscle Wasting, Testicular Atrophy after PubertyAssociated Conditions: Cardiomyopathy , Type II Diabetes Mellitus, Mental Retardation,Decreased Myotonin (transfers phosphate to ATP) 10
  11. 11. Primary HypogonadismCongenital Anorchcia (Vanishing Testis Syndrome)46XY,No Discernable Testicular Tissue in Most, BilateralTesticular Torsion in Utero?HCG Stimulation—Detect Testicular RemnantsSertoli-Cell-Only Syndrome46XY,Germinal Cell Aplasia, FSH>LHTestosterone NormalSertoli Cells Vacuolated—Functional Abnormality? 11
  12. 12. Primary HypogonadismAcquired Germinal Cell AplasiaChemotherapy, Radiation, Environmental Toxins(Dibromodichloralpropane)OrchitisPost-Pubertal Mumps: 40% have Orchitis, 40% withOrchitis have Varying Degrees of Testicular Atrophy,Sperm Count Lower in Most with Atrophy but TrueImpaired Fertility in 15%Autoimmune Orchitis: Type I and II endocrinedeficiencyOthers :Cirrhosis, Chronic Renal Failure, Long-TermGlucocorticoid Therapy 12
  13. 13. Secondary Hypogonadism  GnRH T Normal- LH / FSH T T  Sperm  E2  DHT  Inhibin B 13
  14. 14. DDx :Secondary Hypogonadism congenital :1. Isolated hypogonadotropic hypogonadism2. Kallman’s syndrome3. LH orFSH mutations4. Leptin or leptin receptor mutations5. Gonadotrope receptor mutations6. Hypopituitarism7. CAH 14
  15. 15. Kallmanns syndromeGenetics: Sporadic, Dominant, Recessive, X-linkedEtiology: Absent neural cell adhesion molecule (anosmin) in 10-14%, KAL Gene Point Mutation Hypogonadotropic hypogonadism Anosmia or hyponosmia Somatic abnormality – cleft lip, cleft palate, short metacarpal bone, pes carvus , renal agenesis, urogenital tract defect Neurological abnormality – Uncoordinated eye movement, spatial attention, mental retard, sensoryneural deafness, seizure, cerebellar ataxia, red green color blinnessPrevalence: one in 10,000 15
  16. 16. Secondary HypogonadismIsolated Gonadotrophin DeficiencyNo Somatic Abnormalities, No Anosmia, AbnormalGnRH Receptor in a FewSelective Gonadotrophin DeficiencyIsolated LH Deficiency (Pasqualini syndrome): “Fertile”Eunuch, Absence Virilization with SpermatogenesisIsolated FSH Deficiency: Somewhat Small Testis,Oligospermia to Azospermia, Normal VirilizationCongenital adrenal hypoplasia with hypogonadotropic hypogonadism :X-chromosomal recessive disease, in the majority of patients caused by mutations in the DAX1 gene. (prevalence 1 in 12,500 individuals) 16
  17. 17. Genetic hypogodadotropic hypogonadal syndromes Syndrome Clinical manifestationPrader-Labhart-Willi hypomentia, hypotonia,short stature, Cupid’s-bow mouth, DM, obesityLaurence-Moon Biedl retinitis pigmentosa, obesity, polydactyly, MRMultiple lentigines multiple lentigines, cardiac defect, hypertelorism, short stature, deafness, genital and uro. defectRud MR, epilepsy, congenital icthyosis 17
  18. 18. DDx: Secondary Hypogonadismacquired :1. Hyperprolactinemia2. GnRH analog therapy3. Glucocorticoid therapy4. Critical or Chronic illness5. Diabetes mellitus6. Opiates7. Pituitary mass lesions8. Infiltrative diseases9. Sellar surgery or radiation10.hemochromatosis 18
  19. 19. Hyperprolactinemia (HP) caused by prolactin-secreting pituitary adenomas or drug-induced ; additional causes may be chronic renal failure or hypothyroidism A literature review encompassing more than 300 hyperprolactinemic men found sexual dysfunctions in 88%, The most typical pattern associated ED with a reduced sexual desire. HPRL impairs the pulsatile LH release, which results in a decrease of serum testosterone secretion. It is generally believed that this hypogonadism is the main cause of ED. In fact, it may not explain every case. Serum testosterone is in the normal range in nearly half of the ED patients with marked HPRL. In addition, serum sex hormone- binding globulin is low in hyperprolactinemic males,and there are also testosterone-independent mechanisms, probably mainly set at the level of the brains neurotransmittor systems or deacrease in DHT production 19
  20. 20. Important! There is presently no consensus with regards to the screening for HPRL in ED: systematic determination of serum PRL may be justified since HPRL is a serious but reversible disease, while there is presently no reliable clinical, psychometric or hormonal criteria (including serum testosterone level) allowing to restrict its determination to certain categories of the ED patients without risk of neglecting some HPRLs. International Journal of Impotence Research (2003) 15, 373–377. 20
  21. 21.  It is present in 16% of patients with erectile dysfunction and in approx 11% of men with oligospermia Endocrine. 2003 Feb-Mar;20(1-2):75- 82. 21
  23. 23. Androgen insensitivity synd. The effects that androgens have on the human body virilization, masculinization, anabolism, etc. are the result of androgens bound to androgen receptors, the androgen receptor mediates the effects of androgens in the human body. AIS can result if even one of the steps involved in androgenization is significantly disrupted, as each step is required in order for androgens to successfully activate the AR and regulate gene expression Clinical findings indicative of AIS can be CAIS ,PAIS ,MAIS Laboratory findings include a 46,XY karyotype and normal or elevated postpubertal testosterone , LH , and estradiol levels. 23
  24. 24. Late onsethypogonadim 24
  25. 25. Definition :A clinical and biochemical syndrome associated with advancing age and characterized by typical symptoms and a deficiency in serum testosterone levels. It may result in significant detriment in the quality of life and adversely affect the function of multiple organ systems. The key words in this definition are deficiency in androgen levels , aging, detriment in the quality of life and multiple organ dysfunction. 25
  26. 26. Definition Continued…Other terms: Male Menopause Male Climacteric andropause Androgen Decline in the Ageing Male (ADAM) partial ADAM Ageing Male Syndrome (AMS) 26
  27. 27. Pathophysiology of LOH Hypothalamus & aging 1-number of GnRH secreting neurons decreases 2-decrease in the release of neuropeptide Y(an excitatory peptidergic signal to GnRH secreting neurons) 3-beta receptors become less functional in aged men 4-hypothalamic norepinephrine content decrease with aging 5-diminished GnRH impulse strength is the proximate cause of the relative hypogonadism of old age. 27
  28. 28. continue Pituitary & aging 1-GnRH- receptor-activated voltage-dependent Ca2+ channels are less able to mobilize the Ca2+ needed for LH release 2-stess increase cytokines, (IL-1 alpha), which activate the corticotropicadrenal axis and impair gonadotropin secretion 3-IL-1 alpha reduces both the frequency and amplitude of LH secretion through the intermediary arginine vasopressin (AVP) 4-the stress-related inhibition of pituitary LH secretion is more prominent in aged compared to young men. 28
  29. 29. continue Testes & aging 1-age-associated decrement in testicular steroidogenesis 2-with aging, mean serum testosterone concentrations decrease and circadian rhythmicity is lost 29
  30. 30. Pathophysiology of LOH Lower GnRH pulse amplitude Hypothalamus Attenuation of diurnal pulsatility blunted HPG feedback response to low testosterone Pituitary LH & FSH E Reduced Leydig cell number Testes Impaired Leydig cell function diminished LH feedforward activity on testosterone secretionIncreased SHBG Decreased spermatogenesis T 30
  31. 31. Prevalence of LOH 31
  32. 32.  Between ages 39–70 yr: Free testosterone declined by 1.2%/yr, and albumin-bound testosterone by 1.0%/yr. Sex hormone- binding globulin (SHBG), the major serum carrier of testosterone, increased by 1.2%/yr, with the net effect that total serum testosterone declined more slowly (0.4%/yr) than the free or albumin-bound pools alone. 32
  33. 33. Influence of some biological indexes on sex hormone-binding globulinand androgen levels in ageing or obese males. J Clin Endocrinol Metab 1996; 81: 1821-6. Table 1. Influence of age on hormone levels in menAge Total SHBG (nM) Free Testosterone Testosterone (nM) (nM)25-34 21.4 +/- 5.9 35.5 +/- 8.8 0.43 +/- 0.135-44 23.1 +/- 7.4 40.1 +/- 7.9 0.36 +/- 0.0445-54 21.0 +/- 7.4 44.6 +/- 8.1 0.31 +/- 0.0855-64 19.5 +/- 6.8 45.5 +/- 8.8 0.29 +/- 0.0765-74 18.2 +/- 6.8 48.7 +/- 14.2 0.24 +/- 0.0875-84 16.3 +/- 5.8 51.0 +/- 22.7 0.21 +/- 0.0885-100 13.0 +/- 4.6 65.9 +/- 22.8 0.19 +/- 0.08 33
  34. 34. Prevalence of Low T in Aging Men (T < 2.5 Percentile of Young Men BLSA) 100 90 Total T <325 ng/dL 80 70 Free T Index < 0.153 Percentage 60 50 40 30 20 10 0 20-29 30-39 40-49 50-59 60-69 70-79 ≥ 80 Age Decade 34SM Harman, et al, J Clin Endocrinol Metab 86:724-731, 2001
  35. 35. Longitudinal  T Levels with Age 20 18 (177)Testosterone (144) (nmol/L) 16 (151) (109) 14 (43) (158) 12 10 30 40 50 60 70 80 90 Age (Years)Harman SM, et al, J Clin Endocrinol Metab 86:724-731, 2001. 35
  36. 36. The Hypogonadism in Males (HIM) study : 2006 Based on a TT of <300 ng/dL, 39% of the men were defined as being hypogonadal; for every 10-year increase in age, the risk of hypogonadism increased by 17% 36
  37. 37. Age-specific prevalence ofhypogonadism for enrolled patients (HIM study :2006) 37
  38. 38. Recommendation At present, the diagnosis of treatable hypogonadism ,requires the presence of symptoms and signs suggestive of testosterone deficiency (Level 3, Grade A) European Journal of Endocrinology (2008) 159 507–514 38
  39. 39. Recommendation We recommend making a diagnosis of androgen deficiency only in men with consistent symptoms and signs and unequivocally low serum testosterone levels. (1| OOO) CLINICAL PRACTIC GUIDELINE (The Journal of Clinical Endocrinology & Metabolism 91(6):1995–2010) 39
  40. 40. Massachusetts male aging study (MMAS) The prevalence rate of androgen deficiency at study entry, without consideration of signs or symptoms and with a cut-off TT of 400 ng/dl was estimated to be 25.3%; at followup, the prevalence rate was 39.3% 40
  41. 41. But :Considering the presence of at least three signs or symptoms and TT, the prevalence rates were 6% at baseline and 12% at follow-up 41
  42. 42. The European Male Aging Study (EMAS) Defined by symptoms( poor morning erection, low sexual desire, and erectile dysfunction (ED) ). and biochemical evidence ( TT < 317 ng/dL and free testosterone < 6.34 ng/dL )the prevalence of hypogonadism was estimated at 2.1% overall, increasing from as little as 0.1% in men aged 40 to 49 to 5% in men aged 70 to 79. 42
  43. 43. Boston Area Community Health Study (BACH) used a somewhat strict definition of symptomatic TD and estimated its prevalence at 5.6% nationwide among men aged 30 to 79 years 43
  44. 44. 44
  45. 45. clinical presentation The clinical presentation depends on : (1) age at onset of androgen deficiency, (2) duration of androgen deficiency, (3) the profoundness of the deficiency (4) genetic factors controlling androgen receptor responsiveness reflecting androgen receptor polymorphism and mutations. 45
  46. 46. Fetal development. Depending on when hypogonadism develops, and how much testosterone is present, a child who is genetically male may be born with: Female genitalsAmbiguous genitals — genitals that are neither clearly male nor clearly female Underdeveloped male genitals 46
  47. 47. Puberty Decreased development of muscle mass Lack of deepening of the voice Impaired growth of body hair Impaired growth of the penis and testicles Excessive growth of the arms and legs in relation to the trunk of the body Development of breast tissue (gynecomastia) 47
  48. 48. AFTER PUBERTY : LOHInitiation of problems 48
  49. 49. BARRIERS TO RECOGNITION OF TD Nonspecificity of signs and symptoms Lack of consensus on the definition of TD Lack of confidence in diagnostic tests Nonuse of screeners Perception that TD is difficult to manage 49
  50. 50.  Studies suggest that hypogonadism in adult men is often underdiagnosed and under treated. This may be because the symptoms are easily attributed to aging or other medical causes, or ignored by patients and physicians. In fact, only about 5% of hypogonadal men receive testosterone replacement. 50
  51. 51. Group A: Symptoms and signs suggestive of androgen deficiency in men:1. incomplete sexual development, eunuchoidism, aspermia2. Reduced sexual desire (libido) and activity3. Decreased spontaneous erections4. Breast discomfort, gynecomastia5. Loss of body (axillar and pubic) hair, reduced shaving6. Very small or shrinking testis (especially 5ml)7. Inability to father children, low or zero sperm counts8. Height loss, low-trauma fracture, low bone mineral density9. Reduced muscle mass and strength10. Hot flushes, sweats 51 CLINICAL PRACTIC GUIDELINE
  52. 52. Group B: Symptoms and signs associated with androgen deficiency that are less specific than those in group A1. Decreased energy, motivation, initiative, aggressiveness, self confidence2. Feeling sad or blue, depressed mood, dysthymia3. Poor concentration and memory4. Sleep disturbance, increased sleepiness5. Mild anemia (normochromic, normocytic)6. Increased body fat, body mass index7. Diminished physical or work performance CLINICAL PRACTIC GUIDELINE 52
  53. 53. SexualReduced libidoEDDecreased spontaneous erectionReduced intensity of orgasmOligo- or azoospermiaVery small or shrinking testesHot flushes, sweatsBreast discomfort, gynecomastiaLoss of pubic and axillary hair 53
  54. 54. PsychologicalDepressed moodDiminished energy, vitality, or well-beingPoor concentration and memorySleep disturbanc 54
  55. 55. PhysiologicFatigueIncreased body fatDecreased muscle mass and strengthOsteoporosis or low bone mineral densityAnemia 55
  56. 56. 56
  57. 57. Recommendation The symptom most associated with hypogonadism is low libido (Level 3, Grade A) European Journal of Endocrinology (2008) 159 507–514 57
  58. 58. Recommendation Other manifestations of hypogonadism include: erectile dysfunction, decreased muscle mass and strength, increased body fat, decreased bone mineral density and osteoporosis, and decreased vitality and depressed mood. None of these symptoms are specific to the low androgen state but may raise suspicion of testosterone deficiency. One or more of these symptoms must be corroborated with a low serum testosterone level (Level 3, Grade A) European Journal of Endocrinology (2008) 159 507–514 58
  59. 59. Recommendation We suggest that clinicians measure serum testosterone level in patients with clinical manifestations shown in Table 1A. We suggest that clinicians also consider measuring serum testosterone level when the less specific symptoms and signs listed in Table 1B occur in conjunction with those listed in Table 1A. (2| OOO) CLINICAL PRACTIC GUIDELINE (The Journal of Clinical Endocrinology & Metabolism 91(6):1995–2010)59
  60. 60. Recommendation We recommend making a diagnosis of androgen deficiency only in men with consistent symptoms and signs and unequivocally low serum testosterone levels. (1| OOO) CLINICAL PRACTIC GUIDELINE (The Journal of Clinical Endocrinology & Metabolism 91(6):1995–2010) 60
  61. 61. Definition :A clinical and biochemical syndrome associated with advancing age and characterized by typical symptoms and a deficiency in serum testosterone levels. It may result in significant detriment in the quality of life and adversely affect the function of multiple organ systems. The key words in this definition are deficiency in androgen levels , aging, detriment in the quality of life and multiple organ dysfunction. 61
  62. 62. T measurementT levels vary– Circadian, circannual rhythms, &episodicsecretion– Assay variations– Variations in SHBG concentrations-- Illness, drugs, nutritional deficiency :transiently low Tnot defined cut-off values for normal T levels 62
  63. 63. Day-to-Day Variation in T Levels In hypogonadal men with initial T < 300 ng/dL, 30% had normal T on repeat testing1 In older men with initial T < 250 ng/dL – 20% had average T > 300 ng/dL over 6 months – If average of two samples T < 250 ng/dL, none had average T > 300 ng/dL21Swerdloff RS, et al, J Clin Endocrinol Metab 85:4500-4510, 20002Brambilla DJ, et al, Clin Endocrinol (Oxf) 67:853-862, 2007 63
  64. 64. Circulating Testosterone Albumin- bound T (weak) 54% Bioavailable TSHBG-bound Free T T (tight) 2% 44% Total T 64
  65. 65. Common Alterations in SHBG Affect Total and Free T Analog Levels  SHBG  SHBG  Total T  Total T • Moderate obesity • Aging • Low protein (nephrotic) • Hepatitis, cirrhosis • Hypothyroidism • Hyperthyroidism • Glucocorticoids/progestins • Anticonvulsants • Anabolic steroids • Estrogens • Acromegaly • HIVBhasin S, et al, J Clin Endocrinol Metab 91:1995-2010, 2006 65
  66. 66. Testosterone Assays Affected by changes in SHBG – Total T – Free T by analog assay (~all clinical labs) Not affected by changes in SHBG – Calculated free T and bioavailable T from total T and SHBG – Free T by equilibrium dialysis – Bioavailable T by ammonium sulfate precipitation 66
  67. 67. Medications and low TDecrease Leydig Cell T Production corticosteroids ethanol ketoconazoleBind to the Androgen Receptor spironolactone flutamide cimetidineDecrease Gonadotropin Secretion corticosteroids ethanol estrogens & progestins (Megace) Rx that raise prolactin (opiates, metoclopramide, psychotherapy medication)Decreases Conversion of T to DHT 67 finasteride
  68. 68. Biochemical Definitions of Hypogonadism Society Total Testosterone Guidelines ng/mL ng/dL nmol/L EAA, ISA, <3.40 <340 <12 (mild) ISSAM EAU, ASA, <2.31 <231 <8 (severe) ISSM ES <3.00 <300 <10.4 AACE <2.00 <200 7EAA = European Academy of Andrology; ISA = International Society of Andrology; ISSAM = International Society for the Study of theAging Male; EAU = European Association of Urology; ASA = American Society of Andrology; ISSM = International Society for SexualMedicine; ES = Endocrine Society; AACE = American Association of Clinical Endocrinologists 68
  69. 69. RecommendationA serum sample for totaltestosterone determination shouldbe obtained between 0700 and1100 h (Level 2a, A) European Journal of Endocrinology (2008) 159 507–514 69
  70. 70. Recommendation The most widely accepted parameters to establish the presence of hypogonadism is the measurement of serum total testosterone. There are no generally accepted lower limits of normal. There is, however, general agreement that the total testosterone level above 12 nmol/l (350 ng/dl) does not require substitution. Similarly, based on the data of younger men, there is consensus that patients with serum total testosterone levels below 8 nmol/l (230 ng/dl) will usually benefit from testosterone treatment. If the serum total testosterone level is between 8 and 12 nmol/l, repeating the measurement of total testosterone with sex hormone-binding globulin (SHBG) to calculate free testosterone or free testosterone by equilibrium dialysis may be helpful (Level 2b, Grade A). 70 European Journal of Endocrinology (2008) 159 507–514
  71. 71. Recommendation The measurement of free or bioavailable testosterone should be considered when the serum total testosterone concentration is not diagnostic of hypogonadism, particularly in obese men. There are no generally accepted lower limits of normal for free testosterone for the diagnosis of hypogonadism. However, a free testosterone level below 225 pmol/l (65 pg/ml) can provide supportive evidence for testosterone treatment (Level 3, Grade C). Threshold values for bioavailable testosterone depend on the method used and are not generally available European Journal of Endocrinology (2008) 159 507–514 71
  72. 72. Recommendation Since there are known variations between assay methods, it is imperative that the practitioners utilize reliable laboratories and are acquainted with the reference ranges for testosterone from their local laboratory (Level 2b, Grade A). European Journal of Endocrinology (2008) 159 507–514 72
  73. 73. Recommendation Current immunometric methods for the measurement of testosterone can distinguish between hypogonadism and normal adult men. However, the methods based on mass spectrometry are more accurate and precise (Level 2b, Grade A) and are increasingly recognized as the method of choice for serum testosterone measurement. European Journal of Endocrinology (2008) 159 507–514 73
  74. 74. Recommendation Equilibrium dialysis is the gold standard for free testosterone measurement. Free testosterone assays based on analog displacement immunoassays are widely available but do not give an accurate measurement of free testosterone; thus they should not be used. Alternately, measuring serum SHBG levels together with reliable serum total testosterone levels provides the data necessary for calculating free testosterone levels (Level 2b, Grade A). European Journal of Endocrinology (2008) 159 507–514 74
  75. 75. Recommendation Transient decreases of serum testosterone levels such as those due to acute illnesses should be excluded by careful clinical evaluations and repeated hormone measurement (Level 4, Grade A). European Journal of Endocrinology (2008) 159 507–514 75
  76. 76. Recommendation We recommend confirmation of the diagnosis by repeating measurement of total testosterone and in some patients by measurement of free or bioavailable testosterone level, using an appropriate assay. (1| OOO) CLINICAL PRACTIC GUIDELINE (The Journal of Clinical Endocrinology & Metabolism 91(6):1995–2010) 76
  77. 77. Recommendation We suggest that a diagnosis of androgen deficiency should not be made during an acute or subacute illness. (2| OO) CLINICAL PRACTIC GUIDELINE (The Journal of Clinical Endocrinology & Metabolism 91(6):1995–2010) 77
  78. 78. Other investigation ?Recommendation Hypogonadism (primary or secondary) can occur at all ages including elderly men. (Level 4, Grade A). European Journal of Endocrinology (2008) 159 507–514 78
  79. 79. Recommendation Inpatients at risk or suspected of hypogonadism, a thorough physical and biochemical work-up is necessary (Level 4, Grade A) European Journal of Endocrinology (2008) 159 507–514 79
  80. 80. RecommendationMeasurements of serum LH will assist in differentiating between primary and secondary hypogonadism and serum prolactin is indicated when the serum testosterone is lower than 5.2 nmol/l (150 ng/dl) or when secondary hypogonadism is suspected (Level 3, Grade B) European Journal of Endocrinology (2008) 159 507–514 80
  81. 81. MRI indication? Hyperprolactinemia In the presence of another pituitary hormone deficiency or excess LH below 4 IU/l. A TT <5 nmol/l (<150ng/dL), rather than LH, is the best predictor of a significant structural abnormality such as a macroadenoma Patients complaining of new onset headaches, reduced nocturnal penile tumescence and impotence, who are found on exam to have bitemporal hemianopsia 81
  82. 82. Recommendation Risk factors for hypogonadism in older men may include chronic illnesses (including diabetes mellitus, chronic obstructive lung disease, inflammatory arthritic disease, renal disease, and HIV-related disease), obesity, metabolic syndrome, and hemochromatosis . Such chronic diseases should be investigated and treated (Level 4, Grade A). European Journal of Endocrinology (2008) 159 507–514 82
  83. 83. Recommendation Alterations in other endocrine systems occur in association with aging (i.e., estradiol, growth hormone (GH), and DHEA) but the significance of these changes is not well understood. Determinations of estradiol, thyroid hormones, cortisol, DHEA, DHEA-S, melatonin, GH, and insulin-like growth factor-I are not indicated unless other endocrine disorders are suspected based on the clinical signs and symptoms of the patient (Level 2, Grade A) European Journal of Endocrinology (2008) 159 507–514 83
  84. 84. 84
  85. 85. Recommendation Questionnaires such as Aging Male Symptom Score (AMS) and Androgen Deficiency in Aging Men (ADAM) are not recommended for the diagnosis of hypogonadism because of low specificity (Level 3, Grade B) European Journal of Endocrinology (2008) 159 507–514 85
  86. 86. TD is difficult to manage? 86
  87. 87. 87
  88. 88. Recommendation We recommend against screening for androgen deficiency in the general population. (1| OOO) We suggest that clinicians not use the available case finding instruments for detection of androgen deficiency in men receiving health care for unrelated reasons. (2| OOO) CLINICAL PRACTIC GUIDELINE (The Journal of Clinical Endocrinology & Metabolism 91(6):1995–2010) 88
  89. 89. But : Clinicians should maintain a high index of suspicion of TD in patients with some comorbidities. Even those at-risk patients who report no symptoms typical of hypogonadism require a thorough clinical and biochemical workup for TD National and international guidelines concur in recommending TD screening for men deemed at risk due to coexisting illnesses 89
  90. 90. Screening Indication :Type 2 diabetes mellitusMetabolic syndromeEDOsteoporosis, low trauma fractureTreatment with medications that affect testosterone production or metabolism, eg, glucocorticoids, opioidsModerate to severe COPDSellar mass, radiation to the sellar region, or other diseasesof the sellar regionEnd-stage renal disease, maintenance hemodialysisHIVInflammatory arthritisHemochromatosisInfertility 90
  91. 91. 91
  92. 92. Measurement method? Efforts to create standardization of testosterone assays, agreement on standards for testosterone measurement and accurate reference ranges for testosterone by liquid chromatography mass spectrometry (LC–MS)/MS are being developed. International reference standards, characterization of methodology, and population-based reference ranges for free testosterone by equilibrium dialysis are needed. Consensus on the equilibrium constants for testosterone binding to SHBG and albumin will allow improved calculation of free testosterone 92
  93. 93. 93
  94. 94. Prevalence of Hypogonadism UsingBioavailable Testosterone and Free Androgen IndexFrom Morley JE, Perry HM. Andropause: an old concept in new clothing. Clinics in Geriatric Medicine 2003; Vol 19, No 3.Prevalence of hypogonadism in older men.Age (y) Percent Hypogonadal Baltimore Longitudinal Mayo Clinic Canadian Physicians40-49 2 2 550-59 9 6 3060-69 34 20 4570-79 68 34 7080+ 91 -- -- 94
  95. 95. Biochemical Androgen Deficiency Challenges Low serum total T level − Total T most common and available − Relative to normal range in young men (<280-300 ng/dL but assay-to-assay variability) − T levels variable  Morning, on at least two occasions If  SHBG suspected, free or bioavailable T level Illness, drugs, nutritional deficiency  transiently low T 95
  96. 96. 96
  97. 97. Recommendation Salivary testosterone has also been shown to be a reliable substitute for free testosterone measurements but cannot be recommended for general use at this time, since the methodology has not been standardized and adult male ranges are not available in most hospital or reference laboratories (Level 3, Grade B). European Journal of Endocrinology (2008) 159 507–514 97
  98. 98. Recommendation We suggest the measurement of morning total testosterone level by a reliable assay as the initial diagnostic test. (2|QEEE) CLINICAL PRACTIC GUIDELINE (The Journal of Clinical Endocrinology & Metabolism 91(6):1995–2010) 98
  99. 99. Result ! As the population ages, the burden of testosterone deficiency is expected to grow. The prevalence of low testosterone also increases in men with common co-morbidities, such as obesity(*2.4), diabetes(*2.1), and metabolic syndrome. 99