male hypogonadism, loh,
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HYPOGONADISM:ETIOLOGY EPIDEMIOLOGY PREVALENCE DIAGNOSIS
Rahim Tavakkolnia
urologist
IN THE NAME OF
GOD
1
Hypothalamic-Pituitary-Testis Axis
Inhibin B
2
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
Definition
A decrease in either of the two major functions of the testes: – sperm production
And / or– testosterone production
4
5
Primary Hypogonadism
¯ T
LH / FSH
GnRH
T
¯ Inhibin B¯ DHT
¯ T
¯ Sperm
¯ E2
HY
PER
GO
NA
DO
TR
OPI
C
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
Primary HypogonadismKlinefelter 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
Klinefelter's syndrome
8
Primary HypogonadismXX 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
Primary HypogonadismMyotonic DystrophyAutosomal 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
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
Primary Hypogonadism
Acquired Germinal Cell AplasiaChemotherapy, Radiation, Environmental Toxins(Dibromodichloralpropane)
OrchitisPost-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
¯ T
Normal- LH / FSH
GnRH
T
¯ Inhibin B¯ DHT
¯ T
¯ Sperm
¯ E2
HY
POG
ON
AD
OT
RO
PIC
DDx :Secondary Hypogonadismcongenital :
1. Isolated hypogonadotropic hypogonadism
2. Kallman’s syndrome3. LH orFSH mutations4. Leptin or leptin receptor mutations5. Gonadotrope receptor mutations6. Hypopituitarism7. CAH
14
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
Kallmann's syndrome
15
Secondary HypogonadismIsolated 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
Genetic hypogodadotropic
hypogonadal syndromesSyndrome 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
DDx: Secondary Hypogonadism
acquired :1. Hyperprolactinemia2. GnRH analog therapy3. Glucocorticoid therapy4. Critical or Chronic illness5. Diabetes mellitus6. Opiates7. Pituitary mass lesions8. Infiltrative diseases9. Sellar surgery or radiation 10.hemochromatosis MIX
ED
?
18
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
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
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
MALE HYPOGONADISM DUE TO DEFECTS OF ANDROGEN TARGET ORGANS
Androgen Insensitivity Synd.
22
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
Late onset hypogonadim
24
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
Definition Continued…
Other terms: Male MenopauseMale ClimactericandropauseAndrogen Decline in the Ageing Male (ADAM)partial ADAMAgeing Male Syndrome (AMS)
26
Pathophysiology of LOH
Hypothalamus & aging1-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
continue
Pituitary & aging1-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
continue
Testes & aging1-age-associated decrement in
testicular steroidogenesis2-with aging, mean serum testosterone
concentrations decrease and circadian rhythmicity is lost
29
Pathophysiology of LOH
Hypothalamus
Pituitary
Testes
Reduced Leydig cell numberImpaired Leydig cell functiondiminished LH feedforward activity ontestosterone secretionDecreased spermatogenesis
Lower GnRH pulse amplitudeAttenuation of diurnal pulsatilityblunted HPG feedback responseto low testosterone
T
E
LH & FSH
MIX
ED
Increased SHBG
30
Prevalence of LOH
31
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
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 Testosterone (nM)
SHBG (nM) Free Testosterone (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 +/- 0.0833
34
Prevalence of Low T in Aging Men (T < 2.5 Percentile of Young Men BLSA)
0102030405060708090
100
20-29 30-39 40-49 50-59 60-69 70-79 ≥ 80
Age Decade
Perc
enta
ge
Total T <325 ng/dL
Free T Index < 0.153
SM Harman, et al, J Clin Endocrinol Metab 86:724-731, 2001
35
Longitudinal T Levels with AgeTe
stos
tero
ne (
nmol
/L)
Age (Years)
10
12
14
16
18
20
30 40 50 60 70 80 90
(177)
(144)(151)
(158)
(109)
(43)
Harman SM, et al, J Clin Endocrinol Metab 86:724-731, 2001.
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
Age-specific prevalence ofhypogonadism for enrolled patients
(HIM study :2006)
37
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
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
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
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
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
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
DIAGNOSIS :
44
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
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
Puberty
Decreased development of muscle massLack of deepening of the voiceImpaired growth of body hairImpaired growth of the penis and testiclesExcessive growth of the arms and legs in
relation to the trunk of the bodyDevelopment of breast tissue
(gynecomastia)47
AFTER PUBERTY :LOH
Initiation of problems
48
BARRIERS TO RECOGNITION OF TD
Nonspecificity of signs and symptomsLack of consensus on the definition of TDLack of confidence in diagnostic testsNonuse of screenersPerception that TD is difficult to manage
49
1Studies 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
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 CLINICAL PRACTIC GUIDELINE 51
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
SexualReduced 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 hair53
Psychological
Depressed mood
Diminished energy, vitality, or well-being
Poor concentration and memory
Sleep disturbanc
54
Physiologic
Fatigue
Increased body fat
Decreased muscle mass and strength
Osteoporosis or low bone mineral density
Anemia
55
56
Recommendation
The symptom most associated with hypogonadism is low libido (Level 3, Grade A)
European Journal of Endocrinology (2008) 159 507–514
57
RecommendationOther 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
RecommendationWe 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
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)
2
60
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
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
3
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, 20002Brambilla DJ, et al, Clin Endocrinol (Oxf) 67:853-862, 2007
64
SHBG-bound T (tight)
44%
Albumin-bound T (weak)54%
Free T2%
Circulating Testosterone
Bioavailable T
Total T
65
Common Alterations in SHBGAffect Total and Free T Analog Levels
• Estrogens• HIV
• Anabolic steroids• Acromegaly
• Anticonvulsants• Glucocorticoids/progestins
• Hyperthyroidism• Hypothyroidism
• Hepatitis, cirrhosis• Low protein (nephrotic)
• Aging• Moderate obesity
SHBG Total T
¯ SHBG Total T
Bhasin S, et al, J Clin Endocrinol Metab 91:1995-2010, 2006
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
Medications and low TDecrease Leydig Cell T Production
corticosteroidsethanolketoconazole
Bind to the Androgen Receptorspironolactoneflutamidecimetidine
Decrease Gonadotropin Secretioncorticosteroidsethanolestrogens & progestins (Megace)Rx that raise prolactin (opiates, metoclopramide,
psychotherapy medication)
Decreases Conversion of T to DHTfinasteride
67
Society Guidelines
Total Testosterone
EAA, ISA, ISSAM
EAU, ASA, ISSM
ES
AACE
ng/mL
<3.40
<2.31
<3.00
<2.00
ng/dL
<340
<231
<300
<200
nmol/L
<12 (mild)
<8 (severe)
<10.4
7
Biochemical Definitions of Hypogonadism
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
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
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).
European Journal of Endocrinology (2008) 159 507–51470
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
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
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) 159 507–51473
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
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) 159 507–51475
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
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
Other investigation ?
RecommendationHypogonadism (primary or secondary) can
occur at all ages including elderly men. (Level 4, Grade A).
European Journal of Endocrinology (2008) 159 507–514
78
Recommendation
In patients 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
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
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
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
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
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
4
85
TD is difficult to manage?
5
86
SCREENING
87
RecommendationWe 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
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
Screening Indication :Type 2 diabetes mellitusMetabolic syndromeED
Osteoporosis, low trauma fracture Treatment with medications that affect testosterone
production or metabolism, eg, glucocorticoids, opioidsModerate to severe COPDSellar mass, radiation to the sellar region, or other diseases of the sellar regionEnd-stage renal disease, maintenance hemodialysisHIVInflammatory arthritisHemochromatosis
Infertility 90
THANK YOU 91
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
Prevalence of Hypogonadism Using Bioavailable 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
Physicians
40-49 2 2 550-59 9 6 3060-69 34 20 4570-79 68 34 7080+ 91 -- --
94
95
Biochemical Androgen Deficiency
ChallengesLow 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 occasionsIf SHBG suspected, free or bioavailable T
levelIllness, drugs, nutritional deficiency
transiently low T
96
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
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
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
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