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

1. HYPOGONADISM:
ETIOLOGY
EPIDEMIOLOGY
PREVALENCE Rahim Tavakkolnia
DIAGNOSIS urologist
1

2. Hypothalamic-Pituitary-Testis Axis
Inhibin B
2

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. Definition
 A decrease in either of the two major
functions of the testes:
– sperm production
And / or
– testosterone production
4

5. Primary Hypogonadism
 GnRH
T
 LH / FSH
T
T  Sperm
 E2  DHT  Inhibin B
5

6. DDx: Primary Hypogonadism
1. Klinefelter Syndrome
2. XX Male (Sex Reversal)
3. Noonan Syndrome (Male Turner Syndrome)
4. Myotonic Dystrophy
5. Congenital Anorchia (Vanishing Testis
Syndrome)
6. Sertoli-Cell-Only Syndrome
7. Acquired Germinal Cell Aplasia
8. Orchitis
9. Others : CRF, Cirrhosis, HIV, Drugs, XRT,
6

7. Primary Hypogonadism
Klinefelter Syndrome
46 XXY, 46 XY/XXY, 48 XXXY
1 in 500 men
Eunuchoid 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 Azospermia
Associated Conditions: COPD, Cancer of Breast, Germ
Cell Tumors, Autoimmune Diseases, Diabetes Mellitus,
Osteopenia, Mitral Valve Prolapse, Mental Slowness,
Antisocial Behavior
7

8. Klinefelter's
syndrome
8

9. Primary Hypogonadism
XX Male (Sex Reversal)
Translocation of the SRY gene,
Shorter than Average, Normal Intelligence,
Gynecomastia, Small Testis, Azospermia
Noonan Syndrome (Male Turner Syndrome)
46 XY,
Short Stature, Webbed Neck, Shield Chest, Small
Testis, Impaired Spermatogenesis, May Have Low
Testosterone
Associated Conditions: Mental Retardation, Pulmonary
Stenosis, Hypertrophic Cardiomyopathy,
9

10. Primary Hypogonadism
Myotonic Dystrophy
Autosomal Dominant
Inability to Relax Striated Muscle, Frontal Balding,
Ptosis , Cataracts , Atrophy of Facial Muscles , Distal
Muscle Wasting,
Testicular Atrophy after Puberty
Associated Conditions: Cardiomyopathy , Type II
Diabetes Mellitus, Mental Retardation,
Decreased Myotonin (transfers phosphate to ATP)
10

11. Primary Hypogonadism
Congenital Anorchcia (Vanishing Testis Syndrome)
46XY,
No Discernable Testicular Tissue in Most, Bilateral
Testicular Torsion in Utero?
HCG Stimulation—Detect Testicular Remnants
Sertoli-Cell-Only Syndrome
46XY,
Germinal Cell Aplasia, FSH>LH
Testosterone Normal
Sertoli Cells Vacuolated—Functional Abnormality?
11

12. Primary Hypogonadism
Acquired Germinal Cell Aplasia
Chemotherapy, Radiation, Environmental Toxins
(Dibromodichloralpropane)
Orchitis
Post-Pubertal Mumps: 40% have Orchitis, 40% with
Orchitis have Varying Degrees of Testicular Atrophy,
Sperm Count Lower in Most with Atrophy but True
Impaired Fertility in 15%
Autoimmune Orchitis: Type I and II endocrine
deficiency
Others :
Cirrhosis, Chronic Renal Failure, Long-Term
Glucocorticoid Therapy 12

13. Secondary Hypogonadism
 GnRH
T
Normal- LH / FSH
T
T  Sperm
 E2  DHT  Inhibin B
13

14. DDx :Secondary Hypogonadism
congenital :
1. Isolated hypogonadotropic
hypogonadism
2. Kallman’s syndrome
3. LH orFSH mutations
4. Leptin or leptin receptor mutations
5. Gonadotrope receptor mutations
6. Hypopituitarism
7. CAH 14

15. Kallmann's syndrome
Genetics: Sporadic, Dominant, Recessive, X-linked
Etiology: 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 blinness
Prevalence: one in 10,000 15

16. Secondary Hypogonadism
Isolated Gonadotrophin Deficiency
No Somatic Abnormalities, No Anosmia, Abnormal
GnRH Receptor in a Few
Selective Gonadotrophin Deficiency
Isolated LH Deficiency (Pasqualini syndrome): “Fertile”
Eunuch, Absence Virilization with Spermatogenesis
Isolated FSH Deficiency: Somewhat Small Testis,
Oligospermia to Azospermia, Normal Virilization
Congenital 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. Genetic
hypogodadotropic
hypogonadal syndromes
Syndrome Clinical manifestation
Prader-Labhart-Willi hypomentia, hypotonia,short stature,
Cupid’s-bow mouth, DM, obesity
Laurence-Moon Biedl retinitis pigmentosa, obesity, polydactyly,
MR
Multiple lentigines multiple lentigines, cardiac defect,
hypertelorism, short stature, deafness,
genital and uro. defect
Rud MR, epilepsy, congenital icthyosis
17

18. DDx: Secondary Hypogonadism
acquired :
1. Hyperprolactinemia
2. GnRH analog therapy
3. Glucocorticoid therapy
4. Critical or Chronic illness
5. Diabetes mellitus
6. Opiates
7. Pituitary mass lesions
8. Infiltrative diseases
9. Sellar surgery or radiation
10.hemochromatosis 18

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 brain's neurotransmittor systems or deacrease in
DHT production
19

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.  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

22. MALE HYPOGONADISM
DUE TO DEFECTS OF
ANDROGEN TARGET
ORGANS
Androgen Insensitivity Synd.
22

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. Late onset
hypogonadim
24

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. Definition Continued…
Other terms:
Male Menopause
Male Climacteric
andropause
Androgen Decline in the Ageing Male (ADAM)
partial ADAM
Ageing Male Syndrome (AMS)
26

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. 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. 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. 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 secretion
Increased SHBG Decreased spermatogenesis
T
30

31. Prevalence of LOH
31

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. Influence of some biological indexes on sex hormone-binding globulin
and androgen levels in ageing or obese males. J Clin Endocrinol Metab
1996; 81: 1821-6.
Table 1. Influence of age on hormone levels in men
Age Total SHBG (nM) Free
Testosterone Testosterone
(nM) (nM)
25-34 21.4 +/- 5.9 35.5 +/- 8.8 0.43 +/- 0.1
35-44 23.1 +/- 7.4 40.1 +/- 7.9 0.36 +/- 0.04
45-54 21.0 +/- 7.4 44.6 +/- 8.1 0.31 +/- 0.08
55-64 19.5 +/- 6.8 45.5 +/- 8.8 0.29 +/- 0.07
65-74 18.2 +/- 6.8 48.7 +/- 14.2 0.24 +/- 0.08
75-84 16.3 +/- 5.8 51.0 +/- 22.7 0.21 +/- 0.08
85-100 13.0 +/- 4.6 65.9 +/- 22.8 0.19 +/- 0.08 33

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
34
SM Harman, et al, J Clin Endocrinol Metab 86:724-731, 2001

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. 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. Age-specific prevalence of
hypogonadism for enrolled patients
(HIM study :2006)
37

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. 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. 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. 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. 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. 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

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. 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. 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. AFTER PUBERTY :
LOH
Initiation of problems
48

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.  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. Group A: Symptoms and signs suggestive
of androgen deficiency in men:
1. incomplete sexual development, eunuchoidism, aspermia
2. Reduced sexual desire (libido) and activity
3. Decreased spontaneous erections
4. Breast discomfort, gynecomastia
5. Loss of body (axillar and pubic) hair, reduced shaving
6. Very small or shrinking testis (especially 5ml)
7. Inability to father children, low or zero sperm counts
8. Height loss, low-trauma fracture, low bone mineral
density
9. Reduced muscle mass and strength
10. Hot flushes, sweats
51
CLINICAL PRACTIC GUIDELINE

52. Group B: Symptoms and signs associated with
androgen deficiency that are less specific
than those in group A
1. Decreased energy, motivation, initiative,
aggressiveness, self confidence
2. Feeling sad or blue, depressed mood, dysthymia
3. Poor concentration and memory
4. Sleep disturbance, increased sleepiness
5. Mild anemia (normochromic, normocytic)
6. Increased body fat, body mass index
7. Diminished physical or work performance
CLINICAL PRACTIC GUIDELINE 52

53. Sexual
Reduced libido
ED
Decreased spontaneous erection
Reduced intensity of orgasm
Oligo- or azoospermia
Very small or shrinking testes
Hot flushes, sweats
Breast discomfort, gynecomastia
Loss of pubic and axillary hair
53

54. Psychological
Depressed mood
Diminished energy, vitality, or well-being
Poor concentration and memory
Sleep disturbanc
54

55. Physiologic
Fatigue
Increased body fat
Decreased muscle mass and strength
Osteoporosis or low bone mineral density
Anemia
55

56. 56

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. 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. 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. 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. 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. T measurement
T levels vary
– Circadian, circannual rhythms, &episodic
secretion
– Assay variations
– Variations in SHBG concentrations
-- Illness, drugs, nutritional deficiency :
transiently low T
not defined cut-off values for normal T levels
62

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/dL2
1Swerdloff RS, et al, J Clin Endocrinol Metab 85:4500-4510, 2000
2Brambilla DJ, et al, Clin Endocrinol (Oxf) 67:853-862, 2007 63

64. Circulating Testosterone
Albumin-
bound T
(weak)
54%
Bioavailable T
SHBG-bound
Free T
T (tight)
2%
44%
Total T
64

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 • HIV
Bhasin S, et al, J Clin Endocrinol Metab 91:1995-2010, 2006 65

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. Medications and low T
Decrease Leydig Cell T Production
corticosteroids
ethanol
ketoconazole
Bind to the Androgen Receptor
spironolactone
flutamide
cimetidine
Decrease Gonadotropin Secretion
corticosteroids
ethanol
estrogens & progestins (Megace)
Rx that raise prolactin (opiates, metoclopramide,
psychotherapy medication)
Decreases Conversion of T to DHT 67
finasteride

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 7
EAA = European Academy of Andrology; ISA = International Society of Andrology; ISSAM = International Society for the Study of the
Aging Male; EAU = European Association of Urology; ASA = American Society of Andrology; ISSM = International Society for Sexual
Medicine; ES = Endocrine Society; AACE = American Association of Clinical Endocrinologists 68

69. Recommendation
A serum sample for total
testosterone determination should
be obtained between 0700 and
1100 h (Level 2a, A)
European Journal of Endocrinology (2008) 159 507–514
69

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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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

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. TD is difficult to manage?
86

87. 87

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. 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. Screening Indication :
Type 2 diabetes mellitus
Metabolic syndrome
ED
Osteoporosis, low trauma fracture
Treatment with medications that affect testosterone
production or metabolism, eg, glucocorticoids, opioids
Moderate to severe COPD
Sellar mass, radiation to the sellar region, or other diseases
of the sellar region
End-stage renal disease, maintenance hemodialysis
HIV
Inflammatory arthritis
Hemochromatosis
Infertility
90

91. 91

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

94. Prevalence of Hypogonadism Using
Bioavailable Testosterone and Free Androgen
Index
From 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 Physicians
40-49 2 2 5
50-59 9 6 30
60-69 34 20 45
70-79 68 34 70
80+ 91 -- --
94

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

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. 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. 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