Metabolic Messengers: Testosterone

Testosterone was the first hormone chemically synthesized for replacement therapy, discovered during the endocrine gold rush of the 1930s.

• Testosterone's discovery is historically situated within the broader 'endocrine gold rush' of the 1930s.
• Its synthesis for replacement therapy represents a landmark milestone in endocrinology and therapeutic pharmacology.
• The paper highlights 'key milestones in the history of testosterone's discovery and therapeutic applications.'

Testosterone functions both directly through the androgen receptor (AR) and indirectly as a prohormone converted by aromatase into 17β-oestradiol, which activates oestrogen receptors ERα and ERβ.

• The dual mechanism involves direct AR activation and indirect oestrogenic signaling via aromatase-mediated conversion to oestradiol.
• Testosterone is also metabolized to dihydrotestosterone (DHT), described as 'a potent, non-aromatizable AR agonist,' through steroid 5α-reductases.
• Testosterone and its metabolites signal through both 'AR- and ER-mediated genomic and rapid non-genomic actions.'
• This multi-pathway signaling applies in both male and female organisms.

Testosterone plays an important role in regulating systemic metabolism in both male and female organisms.

• The paper states that 'mounting evidence underscores the importance of testosterone in the regulation of systemic metabolism in both male and female organisms.'
• Evidence is drawn from testosterone replacement therapy studies in humans and mechanistic research in rodent models.
• Metabolic roles extend beyond traditional recognition of testosterone as solely a sex hormone.

Testosterone is presented as a key messenger promoting cardiometabolic health, musculoskeletal integrity, and energy balance.

• The review synthesizes 'current understanding of testosterone as a key messenger promoting metabolic homeostasis in preclinical models and humans.'
• The three primary metabolic domains covered are cardiometabolic health, musculoskeletal integrity, and energy balance.
• Evidence base includes both preclinical (rodent model) mechanistic research and human clinical data from testosterone replacement therapy.
• The paper draws on evidence from testosterone replacement therapy in humans as part of its synthesis of metabolic roles.

Dihydrotestosterone (DHT) is characterized as a potent, non-aromatizable androgen receptor agonist produced via steroid 5α-reductase metabolism of testosterone.

• DHT is produced through the action of steroid 5α-reductases on testosterone.
• DHT is described as 'a potent, non-aromatizable AR agonist,' distinguishing it mechanistically from testosterone itself.
• Because DHT cannot be aromatized, its actions are limited to AR-mediated pathways rather than also contributing to oestrogenic signaling.