Late-onset hypogonadism: metabolic impact

Andrology. 2020 Nov;8(6):1519-1529. doi: 10.1111/andr.12705. Epub 2019 Sep 25.


Background: Obesity and dysglycemia (comprising insulin resistance, the metabolic syndrome and type 2 diabetes), that is diabesity, are associated with reduced circulating testosterone and, in some men, clinical features consistent with androgen deficiency.

Objective: To review the metabolic impact of late-onset hypogonadism.

Methods: Comprehensive literature search with emphasis on recent publications.

Results: Obesity is one of the strongest modifiable risk factors for late-onset hypogonadism, and coexisting diabetes leads to further hypothalamic-pituitary-testicular axis suppression. The hypothalamic-pituitary-testicular axis suppression is functional and hence potentially reversible, and occurs predominantly at the level of the hypothalamus. While definitive mechanistic data are lacking, the evidence suggests that hypothalamic-pituitary-testicular axis suppression is mediated by dysregulation of pro-inflammatory cytokines leading to hypothalamic inflammation. Dysregulation of central leptin and insulin signaling may also contribute. In contrast, recent data challenge the paradigm that estradiol excess is a major contributor to hypothalamic-pituitary-testicular axis suppression. Instead, relative estradiol signaling deficiency may contribute to metabolic dysregulation in men with diabesity. While weight loss and optimization of comorbidities can reverse functional hypothalamic-pituitary-testicular axis suppression, testosterone treatment leads to metabolically favorable changes in body composition and to improvements in insulin resistance.

Discussion: The relationship between diabesity and late-onset hypogonadism is bidirectional. Preliminary evidence suggests that, in carefully selected men, lifestyle measures and testosterone treatment may have additive effects.

Conclusions: While recent research has provided new insights into mechanistic and clinical aspects of diabesity-associated late-onset hypogonadism, more evidence from well-designed large trials is needed to guide the optimal clinical approach to such men.

Keywords: diabetes; late-onset hypogonadism; obesity; testosterone.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Age of Onset
  • Animals
  • Biomarkers / blood
  • Diabetes Mellitus, Type 2 / epidemiology
  • Diabetes Mellitus, Type 2 / metabolism
  • Energy Metabolism*
  • Hormone Replacement Therapy
  • Humans
  • Hypogonadism / diagnosis
  • Hypogonadism / drug therapy
  • Hypogonadism / epidemiology
  • Hypogonadism / metabolism*
  • Insulin Resistance
  • Male
  • Metabolic Syndrome / diagnosis
  • Metabolic Syndrome / drug therapy
  • Metabolic Syndrome / epidemiology
  • Metabolic Syndrome / metabolism*
  • Obesity / epidemiology
  • Obesity / metabolism
  • Prognosis
  • Risk Assessment
  • Risk Factors
  • Testosterone / blood
  • Testosterone / deficiency*
  • Testosterone / therapeutic use


  • Biomarkers
  • Testosterone