ENDOCRINE,  PITUITARY

Testosterone deficiency (hypoandrogenism)

December 7, 2023 / No Comments
  • 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

  1. 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)
  2. Undescended testicles
  3. Mumps orchitis
    • mumps orchitis during adolescence or adulthood, long-term testicular damage may occur.
    • This may affect normal testicular function and testosterone production.
  4. Hemochromatosis
    • Too much iron in the blood can cause testicular failure or pituitary gland dysfunction, affecting testosterone production.
  5. Injury to the Testicles
    • Trauma
  6. Cancer treatment(Chemo/Radio)
    • often temporary, but permanent infertility may occur
  7. 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

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