Hypogonadism – decreased function of the testes, relating to either testosterone or sperm production.
Androgen deficiency – clinical syndrome of symptoms associated with low serum testosterone level
Testosterone physiology
Testosterone is a C19 steroid with a hydroxyl group in the 17 position.
It is primarily synthesised from cholesterol in Leydig cells (via 17-a hydroxylase), and also from androstenedione secreted from adrenal cortex.
Secretion of testosterone from Leydig cells in under control of LH. Testosterone levels can have negative feedback of LH production from pituitary.
Roles of testosterone:
- Important in development for sex differentiation (mesonephric duct stimulation)
- Inhibitory effect on LH
- Develop and maintain secondary sex characteristics
- Protein anabolic growth promoting effect
- Adjunct helping promote spermatogenesis (driven mainly by FSH)
Testosterone binds to the androgen receptor.
In addition in some target cells, testosterone is converted to DHT by 5a-reductase, with DHT binding to the same receptors but it is more potent.
In plasma, testosterone is mostly bound to sex hormone binding globulin (SHBG) and also weakly bound to albumin. Only free testosterone (unbound) is biologically available, but only 1-3 % is free.
Diurnal variations are present in serum testosterone – morning peak and mid-afternoon nadir.
With ageing there are increases in SHBG concentrations, and therefore reduction in free testosterone.
Classification
Primary testicular failure (hypergonadotropic) – testis problem
- Low T, with high LH/FSH (consider fertility, Y chromosome testing, karyotyping)
Secondary testicular failure (hypogonadotropic) – brain problem
- Low T, with low LH/FSH (consider prolactin, Kallmann, pituitary imaging)
(Adult-onset hypogonadism) – mixed
Measuring testosterone
Definition for ‘normal’ is the serum testosterone level found in healthy 20 – 45 year old men.
Deficiency is lower than the 2.5 percentile in early morning samples.
No age-specific reference ranges.
There may be inter-lab variability in immunoassays and accuracy. Mass spectrometry is gold standard but expensive.
The normal reference range (10.4 – 30.1 nmol/L) is derived from healthy young men.
- American statement – below 6.9 nmol/L is hypogonadism, 6.9 – 11.1 equivocal.
- European statement – below 8 nmol/L is hypogonadism, 8 – 12 equivocal.
- Aust PBS – below 6 nmol/L for treatment on 2 x tests, or below 15 with LH > 1.5x normal.
Repeat measuring essentially mandatory unless clearly diagnostic with LH/FSH abnormalities – up to 30 % of men will have normal serum testosterone on repeat assessment.
Measurement of free testosterone seems to be unreliable without a role in current clinical practice.
Measurement of SHBG may be useful with some conditions which markedly affect SHBG levels – increased in hyperthyroidism, liver disease and anti-epileptics, mildly increased with ageing, and suppressed with obesity, insulin resistance and exogenous androgens.
Clinical assessment
Features:
| Non-specific | Organ specific | Sexual |
| Lethargy/fatigue
Decreased energy Low mood Irritability Poor concentration Impaired short term memory Sleepiness Reduced work performance Hot flushes Hair loss |
Bone – osteopenia, osteoporosis, fragility fractures, loss of height
Muscle – reduced strength
Fat – increased adiposity
Breast – gynaecomastia
|
Decreased libido – main symptom
ED
Ejaculatory dysfunction |
Effect of ageing on androgens:
- Mixed testicular and hypothalamic/pituitary influence
- Testosterone levels decline 0.5 – 1 % / year after 30
- SHBG levels rise with age -> less free testosterone
- Production of GnRH/LHRH decreases with age
- High BMI, T2DM and metabolic syndrome associated with low testosterone
- Many medications affect testosterone levels – opioids, glucocorticoids, nicotine, marijuana (and prostate cancer treatments)
History:
- Symptoms of androgen deficiency as above
- Medications – opioids, steroids, anti-depressants, THC
- Medical history
- T2DM, OSA, metabolic syndrome, prostate cancer, BPH/LUTS
- Testicular insults
- Mumps, orchitis, torsion, cryptorchidism, cancer
Examination:
- BMI
- Secondary sexual characteristics – body/facial hair, muscle mass
- Gynaecomastia
- Testicular size, symmetry, descent, varicocele
- DRE
Investigations:
- 2 x early morning testosterone levels at same lab
- FSH / LH
- PSA
- FBC
- Optional / case specific:
- Primary testis failure / hypergonadotropic – karyotyping (Klinefleter), Y chromosome deletions
- Secondary testis failure / hypogonadotropic – prolactin, brain/pituitary MRI
Goals of testosterone replacement:
- Restore testosterone levels to the mid-normal range
- Correct signs and symptoms of androgen deficiency
- Minimise potential risks and side effects of treatment
PBS indication:
- Established pituitary or testicular disorder
- Androgen deficiency
- Over 40
- Not due to age, obesity, cardiovascular disease, infertility or drugs
- Treated by endocrinologist, urologist, sexual health specialist
- Serum testosterone < 6.0 nmol/L on two different tests
- Or testosterone between 6 and 15 with LH > 1.5 x upper limit
Contra-indications:
- Breast cancer
- Advanced or metastatic prostate cancer
Precautions:
- Organ confined prostate cancer, elevated PSA, BPH/LUTS
- Untreated polycythaemia
- Untreated OSA
- Unstable or inadequately treated cardiac disease
- When fertility may be desired in future
Adverse effects:
- Polycythaemia
- PSA elevation
- LUTS exacerbation
- Acne or oily skin
- Impaired spermatogenesis
- Reduced HDL cholesterol
- Gynaecomastia
- Balding
- Weight gain
- Mood and libido fluctuation
Monitoring
- Symptom monitoring
- FBC 3 monthly then annually
- Cholesterol
- PSA monitoring
- Bone density
- Testosterone levels
PSA testing guidelines (AUA):
- PSA should be checked before TRT in men over 40
Ongoing treatment with normal T levels – decide on ongoing PSA testing with shared-decision making
Does testosterone replacement change prostate cancer risk?
Probably not.
Multiple guidelines (EAU, BSSM, ISSM) – no compelling evidence that TRT associated with increased risk of prostate cancer.
- Perhaps more prostate cancer is found with more PSAs being checked.
What if patient has a history of treated prostate cancer?
BSSM – offer TRT to symptomatic men with low testosterone if history of treated PCa (Gleason 7, T1-2, PSA < 10) and one year clear follow up.
AUA – “inadequate evidence to quantify the risk-benefit ratio of testosterone therapy” “negotiated discussion based on perceived potential benefit weighed against limited knowledge of potential risks”
Cardiovascular risk:
Aust – “seems prudent to use TRT with a degree of caution in older men with known cardiovascular disease, especially in men without pathological hypogonadism”
AUA – “it cannot be stated definitively whether TRT increases or decreases risk of cardiovascular events”
