EPGOnline

Pathophysiology

Hypogonadism is characterised by deficient testicular production of testosterone and consequent testosterone deficiency, i.e. suboptimal testosterone levels.1 It is the manifestation of a dysfunction along the hypothalamic-pituitary-gonadal (HPG) axis.1 

The HPG axis dysfunction that gives rise to hypogonadism can be caused by several factors, as outlined in table 1 (modified from The International Society for Sexual Medicine’s Process of Care for the Assessment and Management of Testosterone Deficiency in Adult Men).2

Table 1. Causes of HPG axis dysfunction that results in hypogonadism.2

Hypogonadism because of primary (hypergonadotropic) hypogonadism

Hypogonadism because of secondary (hypogonadotropic) hypogonadism

Congenital

  • Klinefelter’s syndrome (47XXY)
  • Androgen receptor defects
  • Noonan syndrome
  • Cryptorchidism

Congenital

  • Isolated hypogonadotropic hypogonadism
  • Kallmann’s syndrome
  • Prader–Willi syndrome
  • Pasqualini syndrome

Acquired

  • Aging (mixed hypogonadism)
  • Drugs
  • Surgery
  • Autoimmune: Mumps orchitis
  • Metabolic: Haemochromatosis
  • Trauma: Testicular trauma or torsion
  • Testicular infarction
  • Iatrogenic Testicular irradiation

Acquired

  • Endocrine/metabolic disorder
  • Diabetes
  • Obesity
  • Aging (mixed hypogonadism)
  • Drugs
  • Surgery
  • Hyperprolactinaemia
  • Iatrogenic: Hypothalamic–pituitary irradiation
  • Neoplasias: Primary and secondary CNS tumours
Note: the most common acquired causes are underlined.

 

It is well documented and well known that testosterone levels decline with advancing age.3-8 However, as indicated in table 1, hypogonadism can also be caused by an unhealthy lifestyle leading to metabolic disturbances, obesity and type 2 diabetes. In fact, older age, obesity, and diabetes are independent risk factors for hypogonadism and its symptoms, and both chronological aging and changes in lifestyle factors that negatively impact health status are associated with declines in testosterone levels.6,7,9-12

There is research showing that the impact of increasing body fat and waist size on declining testosterone levels can be even more substantial than that of age; body fat/waist size was found to be the most important determinant of differences in total testosterone levels,9 regardless of age.13 This was confirmed in a systematic review and meta-analysis which found that weight loss reverses obesity-induced secondary hypogonadism.14 However, returning to a healthy weight after becoming overweight/obese is very difficult for most men to achieve and sustain. Nevertheless, healthy lifestyle habits should be given more attention as a strategy to prevent development of hypogonadism.

Regardless of the underlying cause of hypogonadism, the treatment approach is aimed at returning testosterone to physiologically normal levels and resolution of symptoms (and signs, if present).