male hypogonadism, loh,

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


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


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

http://www.ncbi.nlm.nih.gov/pubmed/12668871

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

Recommendation

The symptom most associated with hypogonadism is low libido (Level 3, Grade A)


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)


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)


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)


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).


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).


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.


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).


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).


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)


76

Recommendation

We suggest that a diagnosis of androgen deficiency should not be made during an acute or subacute illness. (2| OO)


77

Other investigation ?

RecommendationHypogonadism (primary or secondary) can

occur at all ages including elderly men. (Level 4, Grade A).


78

Recommendation

In patients at risk or suspected of hypogonadism, a thorough physical and biochemical work-up is necessary (Level 4, Grade A)


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)


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).


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)


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)


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

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

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).


97

Recommendation

We suggest the measurement of morning total testosterone level by a reliable assay as the initial diagnostic test. (2|QEEE)


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

male hypogonadism, loh,

Health & Medicine

small testis

definition hypogonadism

primary hypogonadism1

short stature

testis axis inhibin

germinal cell aplasia8

chronic renal failure

degrees of testicular