Male Androgen Deficiency

A/Prof Usman MalabuMBBS, MSC (Chem Path), FWACP, MRCP, FACP, FRACP

Staff Endocrinologist & Year 6 JCU Academic Coordinator

Department of Diabetes & Endocrinology TTH

MALE ANDROGEN DEFICIENCY

A 70 year-old Caucasian male Low testosterone 7 nmol/l

PMH: Type 2 DM, obesity, dyslipidemia, hypertension, low back pain, osteoarthritis and depression

Meds: Metformin XR 2g, Atorvastatin 40 mg OD, Perindopril 4 mg

OD, Fentanyl patch daily Prednisolone 10 mg OD

O/E: BP 130/80, Wt 110 KG, Ht 1.60, BMI 43 kg/m2.

Invs: A1c 7%, Total cholesterol 3 mmol/l, Total Testosterone 7 nmol/l

Group A

Q1. What further history would you inquire?

Q2. What further examination would you do?

Q3. How would you evaluate this patient?

Q4. What is the next step in work up?

Group D 26 year-old male married 6 months with poor erection

Was sexually abstinent & Libido is “fair to poor”

Puberty 15-17 yrs & Exercise tolerance was “good.”

Testes have always been “small”

Negative head trauma, loss of smell, testicular trauma, testicular surgery, or treatment for cancer

The patient denied chronic illness or taking medication

Family history was unremarkable

Exam: Wt 76 Kg, Height 181 cm

Group D

Q13. What further examination would you do?

Q14. How would you evaluate this patient?

Q15. What is the next step in confirming the diagnosis?

Q16. What would be your long-term plan for this patient?

Group B

Q5. List risk factors for hypogonadism in this subject

Q6. What would you do before starting testosterone Rx?

Q7. What are the side effects of testosterone Rx?

Q8. List absolute/relative contraindications to testosterone Rx

Group C

Q9. What conditions require measuring serum T in males?

Q10. What are pros/cons of mode of T Rx of your choice?

Q11. How are you going to monitor the patient on T Rx?

Q12. When would you consider stopping T Rx?

Androgen DeficiencyAndrogen Deficiency

Androgen deficiency is a condition in which tissues do not have enough exposure to androgens for normal function

One in 200 men under 60 years of age suffer from androgen deficiency

Testosterone levels fall with age

At age 65 years, 10% of men have androgen deficiency and this increases to 20% by 70 years

Testosterone and AgeingTestosterone and Ageing

0

5

10

15

20

25

25-34 35-44 45-54 55-64 65-74 75-84 85-100

Age (years)

Tes

tost

ero

ne

leve

l

Androgen deficiency

1 in 10

Range from about 7% between 40-60 years rising to 25% between 60-80 years

Androgen deficiency: symptoms

Decreased libido

Decreased energy

Loss of muscle mass, sex hair – chronic

Bone loss – chronic

Reduced testicular size & sperm count

Gynaecomastia

Diminished muscle mass

Loss of body hair

Abdominal obesity

Gynaecomastia

Testes frequently normal, occasionally small

Physical Signs

Male hypogonadism

Primary hypogonadism Testes Serum Testosterone↓, FSH & LH ↑

Secondary hypogonadism Pituitary gland or Hypothalamus Serum Testosterone↓, FSH & LH ↔ , ↓

Primary testicular failure

Hypothalamus

Pituitary LHFSH

Testosterone

Testis

Insult

Testosterone LH ( FSH)

Causes – testicular disease Klinefelter’s syndrome

Toxin exposure (cancer chemotherapy or radiotherapy, environmental, toxins)

Idiopathic

Defects of testis development

Orchitis

Orchidectomy (advanced prostate cancer)

Evaluation of Men with Androgen Deficiency

Confirmed low testosterone

Check LH+FSH (SA if infertility)

High gonadotropins – 1o Low/low nl gonadotropins – 2o

Karyotype Prolactin, other pituitary hormones, iron studies, sella MRI

Patient 2

How would you evaluate this patient?

Total testosterone: 2 nmol/l (9-35)

Luteinizing hormone (LH): 66 U/L (1.0-9.0)

What is the initial diagnosis?

Primary hypogonadism

What is the next step in work up?

Karyotype: 47 XXY

Klinefelter’s Syndrome

Incidence ~ 1/1,000 live male births

Extra X chromosome, usually 47 XXY

Manifestations Hypogonadism Gynecomastia Behavioral disorders Bronchiectasis/emphysema/bronchitis Mediastinal germ cell tumors Non-Hodgkin’s lymphoma Diabetes mellitus Lower extremity varicosities

Patient 2

How would you manage this patient?

Androgel 5 g topically QD

Counseling regarding infertility and extragonadal manifestations of Klinefelter’s syndrome

Make patient aware of Klinefelter’s support groups

LHFSH

Secondary testicular failure

Hypothalamus

Pituitary

Testosterone

Testis

Insult

TestosteroneLH ( FSH)

Hypothalamic-pituitary Diseases

Pituitary tumour/therapy (surgery, radiation)

Haemochromatosis

Craniopharyngioma

Idiopathic hypogonadotropic hypogonadism, Kallmann’s syndrome

Hyperprolactinemia

Causes of “Male Menopause”

Pituitary/testes decline Excessive alcohol consumption Obesity Smoking Hypertension Medications Poor diet Lack of exercise Poor circulation Psychological problems - depression

These issues are seen in metabolic syndrome & other medical problems

These issues are seen in metabolic syndrome & other medical problems

Look for co-morbidities in non-responders to PDE-5 inhibitors

Depending on co-morbidities:

Hypogonadism 50% Diabetes mellitus 35% LUTS / BPS 22%

Hypertension 23% Hyperlipidaemia Obesity

Yassin et al. IJIR Vol. 14, Suppl. 3, 9/2002

Diagnostic Testing for Androgen Deficiency

Who to test? Only men with consistent symptoms and signs

of unequivocally low serum testosterone levels

Screening in the general population is not recommended

Screening Questionnaires

Androgen Deficiency in the Aging Male Questionnaire

Massachusetts Male Aging Study questionnaire

Both have fair sensitivity (80-90%) but poor specificity (50-60%)

Not generally recommended

Bhasin, S. et al. J Clin Endocrinol Metab 2006;91:1995-2010

Laboratory evaluation

Testosterone and LH levels

>2 early morning samples

Free testosterone – requires validation

Protein binding – Sex hormone binding globulin (SHBG)

Free androgen index T / SHBG Poor empirical validation

35

Circulating Testosterone

SHBG-bound T (tight)

44%

Albumin-bound T (weak)54%

Free T2%

Bioavailable T

Total T

36

Common Alterations in SHBG

Affect Total and Free T Levels

• Estrogens• HIV

• Anabolic steroids• Acromegaly

• Anticonvulsants• Glucocorticoids

• Hyperthyroidism• Hypothyroidism

• Hepatitis, cirrhosis• Low protein (nephrotic)• Aging• Moderate obesity

SHBG Total T

SHBG Total T

St Louis ADAM questionnaireAndrogen Deficiency in Ageing Males

1. Decrease in sex drive

2. Lack of energy

3. Decrease in strength &/or endurance

4. Lost height

5. Decreased enjoyment of life

6. Sad &/or grumpy

7. Erections less strong

8. Deterioration in sports ability

9. Falling asleep after dinner

10. Decreased work performance

Answering yes to questions 1 or 7, or any other 3 questions indicates a high likelihood of having a low testosterone level.

Beware that depression may result in a high score

Beware that depression may result in a high score

Equilibrium dialysis (gold standard) is very expensive and not readily obtainable

Analog free testosterone is inaccurate and should NOT be used

Calculate bioavailable testosterone using derived formula

Diagnostic Testing for Androgen Deficiency

www.issam.ch/freetesto.htm

Variation in serum total testosterone concentrations

Bremner, WJ, Vitiello, V, Prinz, PN, J Clin Endocrinol Metab 1983; 56:1278

PBS criteria for testosterone therapy

Established pituitary/testicular disorder

Male 40y, no established disorder Not due to aging 2 early am samples, different mornings Testosterone level

< 8 nmol/l 8-15 nmol/l plus LH > 1.5 x upper limit

Micropenis, delayed puberty < 18y

42

Testosterone Formulations

Intramuscular T Extensive experience, inexpensive High-normal T, mood swings or libido, pain

T Patch Low-normal T, skin irritation, expensive

T Gel Low- to high-normal T, flexibility, no irritation Contact transfer, expensive

Buccal T Twice daily, altered taste, gum irritation

Choice often left up to patient

Monitoring: When to refer to Urologist

PSA > 4 ng/ml

Increase in PSA > 1.4 ng/dl within 12 months Rx

Abnormal DRE

Increase in IPSS prostate symptom score > 19

Bhasin, S. et al. J Clin Endocrinol Metab 2006;91:1995-2010

46

Summary: Diagnosis of Male Hypogonadism

Symptoms/signs of androgen deficiency− Sex (erections)− Brain (libido, mood, memory, hot flush/sweats)− Body (muscle, bone, breast and hair)

Consistently low T level x 2

Free or bioavailable T, if suspect SHBG

R/o reversible illness, drugs, nutritional deficiency

LH and FSH 1O vs 2O hypogonadism

47

Conclusions: Hypogonadism in Older Men

Common disorder

Nonspecific clinical findings affected by age, severity and duration of T and co-morbidities

Diagnosis confirmed by repeated T Accurate free T, if SHBG suspected R/O reversible causes

LH and FSH 1o vs 2o hypogonadism

T treatment if benefits > risks

Injectable, patch, gels, buccal T available

Thank You