Testosterone Deficiency (Hypogonadism) in Male by Dr Shahjada Selim

1. TESTOSTERONE
DEFICIENCY IN MALE
Dr Shahjada Selim
Assistant Professor
Department of Endocrinology
Bangabandhu Sheikh Mujib Medical University, Dhaka
Email: selimshahjada@gmail.com, info@shahjadaselim.com

2. • Testosterone (T) is the principal male sex
hormone.
• In men, this anabolic steroid plays a key role
in the development of male reproductive
tissues such as the testis and prostate as well
as promoting secondary sexual
characteristics.
INTRODUCTION:

3. • In adult males, levels of testosterone are
about 7–8 times as great as in adult females.
INTRODUCTION:

5. Testosterone and its Metabolites
Sexual differentiation
Musculature
Bone mass
Erythropoiesis
Psychotropicaction
Potency/libido
Lipid metabolism
Bone mass
Epiphyseal closure
Psychotropicaction
Lipid metabolism
Feedback action
Prostate
Sexual differentiation
Secondaryhair
Sebum production
Prostate
Testosterone
Dihydrotestosterone Oestradiol

6. Binding of testosterone (T)
T firmlyboundto
SHBG
60%
BIOAVAILABLETESTOSTERONE= Albumin-boundT
+FreeT
Free TT looselyboundto
albumin
2%38%

7. T Measurement
T levels vary
– Circadian 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
7

8. When should you measure testosterone?1
Circadianrhythmoftestosterone
1. NieschlagE & BehreHM.Andrology,Malereproductivehealthanddysfunction(2ndEdition).Springer, Heidelberg;2002.

9. 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
9

10. 10
CommonAlterations in SHBG
Affect Total and Free TAnalog 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

11. 11
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

12. 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
finasteride
12

13. Change of Nomenclature
• Over time name of the condition changes
• Men Andropause> Late onset Hypogonadism
(LOH)>
• Testosterone Deficiency (TD)
• In March 2014, ISSM Testosterone Guideline
Committee in New York opined a new generally
accepted definition, Testosterone Deficiency (TD)
to replace the other inconsistent definition like
• Hypogonadism, (primary, secondary, mixed)
• LOH, androgen deficiency, andropause etc

14. ISSM definition of Testosterone Deficiency
(TD)
• ISSM has defined Testosterone Deficiency
(TD) as
• A clinical & biochemical syndrome
characterized by a deficiency of
testosterone, or testosterone action and
relevant symptoms and signs.
(Dean et al; J sex Med 2015; 12: 1660-1686)

15. • TD may affect the function of multiple
organ systems, and result in significant
impacts, determine in the quality of life,
including alterations in sexual functions.
(Dean et al; J sex Med 2015; 12: 1660-1686)

16. Clinical picture of testosterone deficiency1
• Decreased muscle
bulk/power
• Abdominal obesity
• Loss of libido
• Hot flushes/palpitations
• Decreased body hair
• Anaemia
• Subfertility
• Subnormal genital size
• Loss of pubic hair
• Erectile dysfunction
• Sexual dysfunction
• Depression
• Reduced well-being
• Low self esteem
• Poor concentration/drive
General body effects
Reproductive system
Emotional Complications
• Osteoporosis
• Raised lipids
• Insulin resistance
• Sarcopaenia
1. NieschlagE andBehreHM.Testosterone:action,deficiency,substitution(3rd Edition).CambridgeUniversityPress;2004.

17. 18

18. Sex hormones and TD
1. JöckenhovelF. MaleHypogonadism.UNI-MED, Bremen;2004.
LHFSH
GnRH
Hypothalamus
Pituitary
Testis
SECONDARYTD
Secondarytesticularfailure
Hypogonadotrophichypogonadism
PRIMARYTD
Primarytesticular failure
Hypergonadotrophic hypogonadism

19. 20
Primary TD
 T
 LH / FSH
 GnRH
T
 Inhibin B DHT
 T
 Sperm
 E2

20. DDx: Primary TD
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,
21

21. 22
Secondary TD
 T
Normal- LH / FSH
 GnRH
T
 Inhibin B DHT
 T
 Sperm
 E2

22. DDx :Secondary TD
Congenital:
1. Isolated hypogonadotropic TD
2. Kallman’s syndrome
3. LH or FSH mutations
4. Leptin or leptin receptor mutations
5. Gonadotrope receptor mutations
6. Hypopituitarism
7. CAH
23

23. DDx: Secondary TD
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
24

24. TD DUE TO DEFECTS OF ANDROGEN
TARGET ORGANS
Androgen Insensitivity Syndrome (AIS)
25

25. Androgen insensitivity syndrome (AIS)
• 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
26

26. Androgen insensitivity syndrome (AIS)
•Laboratory findings include a 46,XY
karyotype and normal or elevated
postpubertal testosterone, LH and
estradiol levels.
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.
28

28. Late-onset hypogonadism
• A clinical and biochemical syndrome associated with advancing age
and characterised by typical symptoms and a deficiency in serum
testosterone levels1,2
0
25
50
75
25-34
(n=45)
35-44
(n=22)
45-54
(n=23)
55-64
(n=43)
65-74
(n=47)
75-84
(n=48)
75=100
(n=21)
1. NieschlagE et al. EurUrology2005;48:1-4.
2. VermeulenA et al. JClinEndocrinolMetab1996;81:1821-1826.
SHBG Free T (x100) Testosterone
Hormonelevel(nmol/L)
Age

29. Pathophysiology of LOH
Hypothalamus
Pituitary
Testes
Reduced Leydig cell number
Impaired Leydig cell function
diminished LH feedforward activity on
testosterone secretion
Decreased spermatogenesis
Lower GnRH pulse amplitude
Attenuation of diurnal pulsatility
blunted HPG feedback response
to low testosterone
T
E
LH &
FSH
Increased SHBG
30

30. 31
Longitudinal  T Levels with Age
Testosterone
(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.

31. TD 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%
32

32. TD incidence and age (US data)
0
5
10
15
20
25
Overall 48-59 60-69 70-79
Incidence
per1,000person-years
Age(years)
• Expected481,000new casesp.a.in US men 40-69yrs
1. AraujoA et al. JClinEndocrinolMetab2004;89(12):5920-5926.

33. Age-specific prevalence of TD for enrolled patients
(HIM study :2006)
34

34. 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%
35

35. 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
36

36. 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.
37

37. 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
38

38. Prevalence of hypogonadism in DM
0
10
20
30
40
50
Free T Total T Bioavailable T
Percentageofpatients
1. DhindsaS et al. JClinEndocrinolMetab2004;89(11):5462-5468.
• n=103 men with type 2 diabetes

39. Hypogonadism in diabetic vs
nondiabetic men with ED1
22.3
34.0
All ages
ED no diabetes Diabetes
0
10
20
30
40
50
30-39 40-49 50-59 60-69 >70
Age (Years)
%Hypogonadism(T<12nmol/L)
p <0.0001
p <0.0001
1. CoronaG et al. EurUrol2004;46(2):222-228.
n=1027men with ED with and without type 2 diabetes mellitus
+ ED

40. DIAGNOSING TD

41. Recommendation
• At present, the diagnosis of treatable TD,
requires the presence of symptoms and
signs suggestive of testosterone deficiency
(Level 3, Grade A)
European Journal of
Endocrinology (2008) 159 507–514
42

42. 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)
43

43. Specific symptoms:
- Incomplete or delayed sexual development
- Reduced sexual desire.
- Decrease spontaneous erections
- Breast discomfort of gynecomastia.
- Loss of body (axillary, and pubic) hair reduced
shaving.
- Small < 5 ml or shrinking testicles
- Inability to father children, low to zero sperm count
- Height loss, or bone fracture
- Hot flushes, sweats.
MEASUREMENT OF SERUM TESTOSTERONE IN
PATIENTS WITH CLINICAL MANIFESTATIONS

44. 6 | ISSM Quick Reference Guide on Testosterone Deficiency
for men
Erectile dysfunction, hypoactive sexual desire,
osteoporosis, other potential symptoms or signs of
TD or at-risk patient
History, physical examination
and Morning Total Testosterone
(TT)
Low or borderline low T; T<12nmol/l
(346ng/dL)
Normal T; T>12nmol/l
(346ng/dL)
Repeat TT + LH, SHBG,
PRL
No TD-seek other
causes
T 8-12nmol/l (231-
346ng/dL)
+/- SHBG, bother ++
TD if T<8nmol/l
(<346ng/dL)
Normal T; T>12nmol/l
(<346ng/dL)
High
LH
Low/Normal
LH
Exclude
contraindications
Investigate pituitary + other
causes
Reassess, consider
referral or trial of
TRT
Trial of TRT
Lifestyle
modification
No
identifiable
cause
Identified
cause
Successful
Monitor TT,
FBC
Failure
Review
diagnosis
Manage cause
Figure 1: Flow chart for the processof care for the assessmentand management of testosterone deficiency in adult men

45. Patients with borderline testosterone
levels (8-12 nmol/l)1,2
• Consider additional biochemical tests
• Gonadotrophins, SHBG, prolactin
• Careful consideration of comorbidities
• Calculate free testosterone (see online calculator
at www.issam.ch/freetesto.htm)
• Counsel patient regarding treatment options
1. NieschlagE et al.Eur Urol 2005;48:1-4.
2. BhasinS et al.J ClinEndocrinolMetab2006;91(6):1995-2010.

46. MANAGEMENT OF TD

47. Who should receive testosterone treatment?
• Men with clinical symptoms and testosterone <8
nmol/l1
• Men with clinical symptoms and testosterone 8-12
nmol/l where additional investigations indicate
presence of hypogonadism1
• Older men with significant symptoms
• Long-term risks /benefits have yet to be clearly demonstrated
1. Nieschlag E et al. Int J Androl 2005;28:125-127

48. Who shouldn’t receive testosterone treatment?
Untreated or suspected carcinoma of prostate [PSA
of >4 ng/ml or PSA of 3 ng/ml in patient with high risk
for prostate cancer]
• Moderate to severe symptoms of BPH
• Breast cancer
• Liver tumour
• Significant polycythaemia
• Severe cardiac failure
• Untreated sleep apnoea

49. Treat of TD without Testosterone
• The ISSM Committee recommends that men
who wish to maintain spermatogenesis, fertility ,
and the testosterone volume be referred for
specialist management (e.g., Endocrinologist,
Fertility specialist) until an approved non
testosterone is available.

50. Treat of TD without Testosterone
• Clomiphene Citrate blocks estrogen
receptors in the hypothalamus and pituitary
and increase GnRH, LH, FSH release. But
no consistent effect on seminal parameters
or pregnancy rates.
• Aromatase Inhibitor (AI) is used for 2ndary
hypogonadism as alternative approach to
TRT.

51. Follow Up
• The effect of Testosterone Replacement Therapy
(TRT) on symptoms reduction are assesssed and
enquiry about side effects be made 3, 6 and 12
months after initiating TRT and annually there
after.
• Testes to be covered
• TT (target range is mid point of the reference
range for a young adult)
• Lipid profile
• Hematocrit
• PSA (men above 40 years)

52. Follow-up… conted
• Patient should be monitored every 3-6 months during first
year and at least annually thereafter.
• Each visit careful clinical & andrological evaluation should
be performed.
• Digital Rectal Examination is mandatory (as per the ESSM
guideline)
• PSA, hematocrit mandatory
• Consider prostate biopsy if PSA is more than 4ng/ml, or
PSA concentration>1.4ng/ml within any 12 mo period of
TRT

53. TRT outcomes
• Compared to placebo TRT significantly improved
all aspects of sexual function in the studies of
middle ages and elderly men with low T (T
concentration <12nmol/l, 346ng/dl.
• No EFFECTS observed on TRT if the baseline
Testosterone levels higher than 12 nmol/l

54. TRT outcomes
• More severe hypogonadism more significant or
impressive are the result of improvement.
• Hypogonadism is the main cause of ED in
younger men while it is one of the multifactorial
ED in older ones (like DM, dyslipidemia,
metabolic syndrome, Sp Cord Injury etc)

55. TRT outcomes
• Combination of TRT and PDE5I (sildenafil,
tadalafil ) can be used to improve the outcomes of
PDE5I in hypogonadism.
• TRT is associated with reduction in bone
resorption and increase lumber bone mineral
density.

58. Conclusion: Managing TD
• Sexual function such as libido, erection and
ejaculation are clearly testosterone dependent
with different T-cut off values regarding onset of
clinical symptoms.
• To get maximum effect of TD patients both TRT
and PDE5I (sildenafil, tadalafil) should be given
to get the maximum PDE5I response.

59. Take home message
•No EFFECTS observed on TRT if
the baseline Testosterone levels
higher than 12 nmol/l .

60. Take home message
•Testosterone Deficiency (TD) causes
ED and low libido and after
testosterone replacement therapy both
function improves. Maximum effect
reached after 2-3 months of treatment
with TRT.

61. Take home message
• Oral testosterone (17 alpha methyl
testosterone is not recommended by ISSM
committee on TD due to hepatotoxic side
effects and hepatoma.

62. ISSM Algorithm of TD Management

63. Thank You
MS Ahsan@SASSM2016