Androgen Deficiency in Men

Associate Professor Mathis Grossmann &

Professor Jeffrey D. Zajac
Austin Health

Learning objectives
By the end of this session, students should be able to
recognize the symptoms and signs of androgen deficiency in men
conduct a diagnostic work-up in men with androgen deficiency to
delineate the underlying cause
order and interpret appropriate tests to confirm the diagnosis of
androgen deficiency
understand the difference between classical androgen deficiency
due to pathology of the hypothalamo-pituitary-gonadal axis and
non-specific low testosterone levels due to aging and disease
describe management options for men with androgen deficiency.

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Case 1
Mr. KF, a 24 year-old electrician presents with his wife of 2
years for evaluation of infertility. His wife has a child from a
previous marriage which she conceived without difficulty. She
reports that Mr. KF is quite passive sexually and needs to be
prompted to perform his marital duties. Mr KF agrees he
rarely feels like doing it.
He reports no significant health issues and takes no regular
medications. He recalls a childhood diagnosis of mild
attention deficit disorder.
On physical examination, you note boyish-looking facial
features, and scant pubic hair.

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Case 1
What symptoms and signs of androgen
deficiency does Mr. KL exhibit?
Think of further aspects of the history and
examination findings that will be helpful to
establish a clinical diagnosis of androgen
deficiency
What investigations would be helpful?

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Androgen Deficiency in Men: clinical

assessment and diagnostic approach

Hypothalamus

GnRH

Pituitary

LH

FSH

Testes
Testosterone
Spermatogenesis

Griffin, J.E. & Wilson, J.D. (1998) Disorders of the testes and the male reproductive tract. In: Wilson, J.D., Foster, D.W., Kronenberg, H.M.
& Larsen, P.R., eds, Williams Textbook of Endocrinology, 9th Ed., Philadelphia, W.B. Saunders Co., pp. 819-875

Androgen Deficiency A Clinical Syndrome

Characteristic symptoms and signs
Unequivocally low testosterone levels
Absence of transient or reversible causes of low testosterone
levels

-Symptoms are nonspecific

-What to measure ? Total (TT)or free (FT) Testosterone
-What is normal ? No age related reference ranges
-T assay characteristics Lack of standardization
Inaccuracy in low range

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Androgen Deficiency in Men

General
sense of well being, poor concentration
tiredness, poor stamina
mood change - depression, irritability

Sexual
reduced libido is almost universal
erectile failure (rare)

Organ specific features

reduced muscle mass and strength
osteoporosis and fracture
increased fat mass
gynaecomastia
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Bhasin S, Cunningham GR, Hayes FJ, Matsumoto AM, Snyder PJ, Swerdloff RS, et al. Testosterone therapy in adult men with androgen
deficiency syndromes: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2006
Jul;.91(7):1995-2010. doi: 10.1210/jc.2005-2847

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[Testosterone]

Clinical presentation of male hypogonadism depends on age of onset

1st TM

Partial virilisation
Ambiguous genitalia
Complete deficiency:
Female external genitalia

3rd TM

Pre-Puberty

Adult

Ageing

Micropenis
Cryptorchidism

Images from DeGroot, Textbook

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of Endocrinology, 4th edition

Incomplete pubertal maturation

Testes < 4ml
Eunuchoidal body habitus
Gynaecomastia
Decreased peak bone mass

Decrease in:
- Libido/ sexual desire
- Mood/ libido/ stamina
- Muscle mass/ strength
- BMD
Increased fat mass

Testosterone Assays
Normal serum TT = eugonadal
Low TT: repeat any normal level= eugonadal
Calculated FT(cFT): if TT borderline, SHBG
abnormal to rule out falsely low TT
LH (if elevated) may indicate decreased T
secretion

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Bhasin, JCEM 2006

Causes of Androgen Deficiency

Klinefelters Syndrome
Prevalence 1:660, 25% diagnosed during lifetime;
90% 47, XXY
Early Dx enables speech therapy, educational support
Main feature testes < 4cm, firm (pea-like)
azoospermia
variable severity with ascertainment bias
TT commonly low/normal, LH high
More rapid TT decrease with ageing
Puberty triggers germ cell extinction
Usually infertile, occasionally sperm retrievable with
testicular microdissection
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Andrology Australia

The testis is the most

accessible endocrine organ

Not palpable Anorchism

Bilateral cryptorchidism
< 5 ml Kallmanns syndrome,
hypogonadotropic hypogonadism
Klinefelters syndrome, other
hypergonadotropic syndromes
815 ml Germinal damage: toxins, idiopathic
1520 ml Varicocele, drugs, idiopathic
1020 ml Adult-acquired hypogonadotropic
hypogonadism, senescence
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AACE. Endocr Pract 2002; 8: 44056.

< 10 nmol/L

< 10 nmol/L
< 230 pmol/L

Bhasin
JCEM 2006

Case 1: Further History & Examination

Mr KF reports that his pubertal development has been a bit
slower than his peers. He shaves every three days and is the
tallest in the family. Although he works out at the gym, he
does not bulk up like the other guys. He denies testicular
trauma or infections.
Physical examination reveals slight gynaecomastia. His testes
are pea-sized (4 ml in volume) and firm.

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Case 1: Investigations
Morning fasting total testosterone: 4.7 nmol/L, repeat 5.6
nmol/L (reference range l 12-27 nmol/L)
FSH 23.8 mIU/ ml (reference range l 1.0-9.0 mIU/ml)
LH 14.3 mIU/ ml (reference range 1.0-10.0 mIU/ml)
Chromosomal analysis: 47, XXY pattern
Semen analysis: azoospermia

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Case 2
Mr. ED, a 62 year-old accountant presents because he is unhappy
with his sex life. His libido is strong, but he has difficulty
maintaining an erection. His wife is 15 years younger and unhappy
about his performance. They often argue. He has tried an
expensive intranasal spray that he obtained over the Internet but
it did not work.
He asks about hormone therapy for men.
He has not seen a doctor for years but denies other health
issues. In recent years, he feels more tired and lost some
strength. He smokes 10 cigarettes a day and has a few
stubbies with the mates on weekends.
On examination blood pressure is 150/90 and BMI 30 kg/m2. He
appears well virilised and testicular volume is 25 ml bilaterally.
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Case 2
What symptoms and signs of androgen
deficiency does Mr. ED exhibit?
What other information on history and
examination would be relevant to elicit?
What investigations would be helpful?

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Case 2: Further History & Examination

He does not exercise. He denies headaches or visual
disturbance.
On examination, visual fields are normal to confrontation.
His waist circumference is 105 cm.
He has a right carotid bruit and reduced pedal pulses.

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Case 2: Investigations
Morning fasting total testosterone: 8.4 nmol/L, repeat 7.6
nmol/L (reference range 10-27 nmol/L)
SHBG 22 nmol/L (10-50 nmol/L)
Calculated free testosterone 190 pmol/L, 210 pmol/L (> 230
pmol/L)
FSH 3.2 mIU/ ml (normal 1.0-9.0 mIU/ml)
LH 4.1 mIU/ ml (normal 1.0-10.0 mIU/ml)
Normal prolactin and iron studies
Fasting glucose 7.9 mmol/L, LDL cholesterol 4.5 nmol/L
MRI pituitary shows no abnormality

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Management of Androgen Deficiency

Non Classical Androgen Deficiency

Common in ageing and chronic disease
RCTs limited by small numbers, short duration,
different inclusion criteria, surrogate outcomes
Not powered to assess
-meaningful gains in important health outcomes
-risk of cardiovascular disease or prostate cancer
Risk benefit ratio therefore unknown and likely
different in older men compared to young
hypogonadal males
Safety and efficacy remains to be evaluated in
randomised controlled trials
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Testosterone Therapy

Establish treatment goals

Achieve adequate TT levels
Monitor treatment response
Monitor for adverse effects

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Handelsman & Zajac, MJA 2004

Recent additions:
Testosterone undecanoate (long acting) 3-monthly im injections (less peak and trough cf
T ester
Testosterone gel daily application to skin (less irritation cf patch)
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>

Buglar L. How to treat: Androgens and the ageing male. Australian Doctor. 2005 Apr 29;33-40.

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Contraindications to TRT
TRT contraindicated in men with
evidence of prostate cancer

abnormal Digital Rectal Examination

elevated PSA (> 3ng/ml)
diagnosed prostate cancer

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breast cancer
erythrocytosis (HCT > 52%) or hyperviscosity
untreated obstructive sleep apnoea
severe lower urinary tract symptoms (IPSS >19)
class III or IV heart failure
Desire to have child

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Bhasin, JCEM 2006

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Rhoden NEJM 2004

voiding symptoms, sleep apnoea

*
**

*unnecessary with oral formulation licensed in Australia

**Urology review if PSA >4ng/ml, >1.4ng/ml increase over 12 months, PSA velocity > 0.4 ng/ml/y
Sadovsky R, Dhindsa S, Margo K. Testosterone deficiency: Which patients should you screen and treat? J Fam Pract. 2007 May;56(5):S1-24.

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Back to Case 2: Investigations

Morning fasting total testosterone: 8.4 nmol/L, repeat 7.6
nmol/L (reference range 10-27 nmol/L)
SHBG 22 nmol/L (10-50 nmol/L)
Calculated free testosterone 190 pmol/L, 210 pmol/L (> 230
pmol/L)
FSH 3.2 mIU/ ml (normal 1.0-9.0 mIU/ml)
LH 4.1 mIU/ ml (normal 1.0-10.0 mIU/ml)
Normal prolactin and iron studies
Fasting glucose 7.9 mmol/L, LDL cholesterol 4.5 nmol/L
MRI pituitary shows no abnormality
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Case 2: Mangement

What management issues does the case of Mr ED raise?

What are considerations regarding testosterone therapy?

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Key points
Classical androgen deficiency is underdiagnosed and
undertreated
Diagnosis of androgen deficiency in older men or men with
chronic illness should be stringent
RCTs needed to inform about risk benefit ratio in men with
non-classical androgen deficiency
Emphasis on lifestyle measures and treatment of
comorbidities

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References
American Association of Clinical Endocrinologists, Petak SM, Nankin HR, Spark RF, Swerdloff RS, Rodriguez-Rigau LJ.
American Association of Clinical Endocrinologists Medical Guidelines for clinical practice for the evaluation and treatment of
hypogonadism in adult male patients: 2002 update. Endocr Pract. 2002 Nov-Dec;8(6):440-56.
Bhasin S, Cunningham GR, Hayes FJ, Matsumoto AM, Snyder PJ, Swerdloff RS, et al. Testosterone therapy in adult men with
androgen deficiency syndromes: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2006
Jul;.91(7):1995-2010. doi: 10.1210/jc.2005-2847
Bhasin S, Pencina M, Jasuja GK, Travison TG, Coviello A, Orwoll E, et al. Reference ranges for testosterone in men generated
using liquid chromatography tandem mass spectrometry in a community-based sample of healthy nonobese young men in
the Framingham Heart Study and applied to three geographically distinct cohorts. J Clin Endocrinol Metab. 2011
Aug;96(8):2430-9. doi: 0.1210/jc.2010-3012
Buglar L. How to treat: Androgens and the ageing male. Australian Doctor. 2005 Apr 29;33-40. Available from:
http://www.australiandoctor.com.au/cmspages/getfile.aspx?guid=e5dc243f-8af0-4586-9b0e-7394ce25da13
Handelsman DJ, Zajac JD. Androgen deficiency and replacement therapy in men. Med J Aust. 2004 May;180(10):529-35.
Rhoden EL, Morgentaler A. Risks of testosterone-replacement therapy and recommendations for monitoring. N Engl J Med.
2004 Jan;350(5):482-92.
Sadovsky R, Dhindsa S, Margo K. Testosterone deficiency: Which patients should you screen and treat? J Fam Pract. 2007
May;56(6):S1-24.
Snyder PJ, Peachey H, Berlin JA, Hannoush P, Haddad G, Dlewati A, et al. Effects of testosterone replacement in hypogonadal
men. J Clin Endocrinol Metab. 2000 Aug;85(8):2670-7. doi: 10.1210/jc.85.8.2670

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 Copyright The University of Melbourne 2014

Last updated: March 2013