- is a clinical syndrome that results from failure to
- produce physiological levels of testosterone (androgen deficiency) and abnormal number of spermatozoa due to organic pathology that disrupts one or more levels of the hypothalamicpituitary–testicular (HPT) axis
- prevalence : 1 in 500 men
Androgen physiology
- Testosterone is the predominant androgen in males with 95% being secreted by testicular Leydig cells under the influence of luteinising hormone (LH) from the pituitary gland.
- When total testosterone is low, an elevated luteinising hormone concentration is a sensitive indicator of primary Leydig cell failure
- Low testosterone with inappropriately low, normal or minimally elevated luteinising hormone may indicate hypothalamo-pituitary disease that demands investigation.
- Testosterone in plasma is bound to sex hormone binding globulin, and weakly to albumin. Only non‑bound or free testosterone, representing 1–3% of the total concentration, is biologically available.
- additionally,of the 6 mg of testosterone produced daily the majority is inactivated in the liver and excreted by the kidneys.
- A small amount of testosterone is converted to bioactive metabolites:
- 4% to Dihydrotestosterone via a 5a reductase enzyme
- 0.2% to Oestradiol via the enzyme aromatase
- There is a diurnal variation in serum testosterone therefore sampling should be done between 8 and 10 am.
Aetiology of androgen deficiency
Primary:
- known as primary testicular failure
- originates from a problem in the testicles
- usually elevated FSH and LH levels
Secondary:
- problem in the hypothalamus or the pituitary gland
- may be caused by an inherited (congenital) trait or something that happens later in life (acquired), such as an injury or an infection
- usually low/normal FSH and LH levels
Primary Hypogonadism
- Klinefelter’s Syndrome
- 47, XXY
- the commonest cause of primary hypogonadism is Klinefelter syndrome with a prevalence of 1/600 male births.
- SSx
- Tall, slim and underweight
- Gynecomastia (bilateral and painless)
- Decreased facial hair, but pubic hair abundant
- Long legs and short torso
- Obesity and varicosities may occur in 33% of patients
- Hypergonadotropic Hypogonadism
- Testes small and firm (usually <2.0 cm or 2 ml)
- Penis small
- Azoospermia or Oligospermia (and Infertility)
- Undescended testicles
- Mumps orchitis
- mumps orchitis during adolescence or adulthood, long-term testicular damage may occur.
- This may affect normal testicular function and testosterone production.
- Hemochromatosis
- Too much iron in the blood can cause testicular failure or pituitary gland dysfunction, affecting testosterone production.
- Injury to the Testicles
- Trauma
- Cancer treatment(Chemo/Radio)
- often temporary, but permanent infertility may occur
- Normal aging
- Older men generally have lower testosterone levels than younger men do.
- As men age, there’s a slow and continuous decrease in testosterone production( 0.5–2.0% per year from early adulthood onwards) .
- As levels of sex hormone binding globulin (SHBG) rise with age by 1–2% per year, the decline in free testosterone level is greater and is 2–3% per year.
- age-dependent decrease in testosterone levels is accelerated by accumulation of comorbidities, especially obesity
- As many as 30% of men older than 75 have a testosterone level that is below normal
- Whether or not treatment is necessary remains a matter of debate.
Secondary Hypogonadism
- Kallmann syndrome
- due to abnormal development of the hypothalamus
- usually diagnosed in childhood or adolescence when patients present with pubertal delay
- small firm testes (<4 mL in volume in early adulthood) is highly suggestive and the diagnosis can be confirmed with karyotyping
- This abnormality is also associated with the impaired development of the ability to smell (anosmia).
- Pituitary disorders/tumor
- Pituitary adenoma
- Panhypopituitarism (postsurgery or radiotherapy)
- Prolactinoma
- Inflammatory disease (sarcoidosis, Histiocytosis, and tuberculosis)
- involve the hypothalmus and pituitary gland and can affect testosterone production, causing hypogonadism.
- metabolic syndrome
- type 2 diabetes mellitus
- obesity
- Aromatase enzyme, expressed in adipocytes, converts testosterone into 17β-estradiol.
- 17β-estradiol exerts its negative feedback on gonadotropin secretion and leads to testosterone decrease.
- Alteration of testosterone/17β-estradiol ratio brings to a compensatory synthesis of sex-hormone binding glubulin, which binds testosterone in the bloodstream
- depression
- obstructive sleep apnoea
- plasma testosterone levels raise with the sleep onset, they then have a spike at the first REM sleep episode, and continue to rise until awakening.
- Testosterone levels decrease when REM latency is longer, such as in old age and in sleep disorders.
- The sleep fragmentation disrupts testosterone rhythm
- OSAS is associated with a decreased gonadal function, because of less REM sleep episodes and major sleep fragmentation, which contribute to an alteration of gonadotrophin-releasing hormone pulsatility
- chronic kidney disease
- anorexia nervosa
- Stress-induced Hypogonadism
- Stress, excessive physical activity, and weight loss have all been associated with hypogonadism
 | Two-sided relationship between OSA, obesity, and testosterone level. OSAS and obesity contribute to reduce testosterone level in bloodstream; at the same time, lower testosterone level worsens obesity and sleep disorders. OSA, obstructive sleep apnea; OSAS, OSA syndrome |
Partial/Transient
- Acute illness
- Chronic disease
- ESRF
- COPD
- HIV
- T2DM
- Medications
- Potent analgesics especially opioids
- Systemic glucocorticoids
- Androgen deprivation therapy (GnRH agonists)
- Anabolic steroids
Clinical features:
Prepubertal hypoandrogenism
- microphallus
- small testes
- delayed puberty
- long bone growth leading to eunuchoid proportions (arm span exceeding height by 5 cm)
- due to failure of closure of the epiphyseal growth plates
- Features of of Klinefelter syndrome
Postpubertal onset hypoandrogenism
- General
- Lethargy, fatigue
- Low mood
- poor concentration
- impaired short term memory
- decreased energy and motivation
- reduced muscle bulk and strength
- Organ specific
- Bone: osteopaenia, osteoporosis
- Muscle: loss of skeletal muscle especially pectoral girdle
- Gynaecomastia
- Sexual/reproductive
- Decreased libido
- Erectile dysfunction/decreased spontaneous erections (uncommon)
- SSx of pituitary mass effect
- headache
- visual field defect
- eye movement disturbance
- features of hypopituitarism or of a hormone producing pituitary tumour
- eg. Cushing’s syndrome
Endocrine laboratory assessment
- Routine screening for hypogonadism in asymptomatic men is not recommended
- Most circulating testosterone is bound to carrier proteins
- 44% tightly to sex hormone binding globulin [SHBG]
- 54% loosely to albumin
- Therefore this protein binding, evaluation of free testosterone levels (and thus the presumed biologically active fraction) has been proposed to correlate better with clinical features of hypoandrogenism.
- However, the clinical value of free testosterone estimates is unclear
- Best method in assessing androgenic status serum total testosterone.
- Measurements should be performed in the morning because of the circadian nature of testosterone production.
- levels:
- 11.1 nmol/L is normal
- below 6.9 nmol/L is diagnostic of hypogonadism
- 6.9–11.1 nmol/L is equivocal
Clues to androgen abuse:
- muscular build
- low HDL level
- higher than expected haematocrit
Testosterone therapy
- Testosterone therapy should not be started without a thorough work-up to delineate the underlying aetiology and identify associated pathologies.
- Older obese men with chronic comorbidities commonly present with non-specific symptoms and modestly low testosterone. In such men emphasis should be on weight loss and optimisation of comorbidities.
- The risk–benefit ratio of testosterone therapy in such men is less favourable than in men with organic androgen deficiency.
- Testosterone replacement is recommended for symptomatic classical androgen deficiency syndromes after excluding contraindications in the initial work up
- Men with organic hypogonadism respond very well
- marked improvement in sexual function
- sense of well being and energy levels
- maintenance of secondary sexual characteristics.
- Rx does not improve fertility
- testosterone therapy may cause gonadotropin suppression and supress spermatogenesis.
- erectile dysfunction
- Androgen deficiency and erectile dysfunction are two overlapping conditions with distinct pathophysiology.
- A randomised, placebo-controlled trial studied the effect of testosterone therapy added to sildenafil in erectile dysfunction.
- The results showed that sildenafil plus testosterone was not superior to sildenafil plus placebo, although pre-treatment testosterone levels in such men were not unequivocally low
- PBS subsidises Testosterone ‘on authority’ for males with
- Established pituitary or testicular disease
- Men over 40 years old without such disorders if:
- serum total testosterone must be below 8 nmol/L, or
- below 15 nmol/L in association with concentrations of serum luteinising hormone more than 1.5 times the upper limit of normal.
- To qualify for subsidised treatment, the patient must have a low testosterone on at least two occasions
- Contraindications to testosterone therapy
- Breast or prostate cancer
- A palpable prostate nodule or induration without further urological evaluation
- PSA >4 ng/mL (or >3 ng/mL in men at high risk of prostate cancer) without further urological evaluation
- Severe lower urinary tract symptoms (International prostate symptom score >19)
- Haematocrit >50%
- Untreated severe obstructive sleep apnoea
- Uncontrolled or poorly controlled heart failure
- When fertility is desired
- Adverse effects of testosterone therapy
- More common
- Erythrocytosis –> can increase the risk of cardiovascular events, so haematocrit should be checked before initiation and annually during therapy
- Acne and oily skin
- Detection of subclinical prostate cancer
- Growth of metastatic prostate cancer
- Reduced sperm production and fertility
- Uncommon
- Gynaecomastia
- Male pattern balding (familial)
- Growth of breast cancer
- Induction or worsening of obstructive sleep apnoea
- More common
