The physiology of growth hormone (GH) in adults: translational journey to GH replacement therapy.

Growth hormone plays an important regulatory role in substrate metabolism, sodium homeostasis, body composition, and physical function in adult life.

• GH-induced anabolism is achieved by stimulating amino acid incorporation into protein while reducing oxidative loss.
• GH simultaneously enhances lipid utilisation by stimulating fatty acid oxidation and reducing lipid storage.
• Sodium and fluid retention are enhanced by activating the renin-angiotensin system and distal renal tubular reabsorption.
• GH stimulates both the aerobic and anaerobic energy systems that underpin muscle and cardiovascular function.

Adult GH deficiency (GHD) produces a clinical picture of increased adiposity, reduced lean mass, and impaired physical and psychological function.

• These manifestations are explained by the pleiotropic actions of GH across multiple physiological systems.
• All of these clinical features are reversed when GH is replaced.
• GHD is identified by rigorously validated diagnostic tests.
• The recognition that GH plays an important role in adult health requiring replacement therapy has only occurred in the last three decades.

Women require a greater replacement dose of GH than men.

• This sex difference in GH dosing requirement is attributed to differential effects of sex steroids on GH action.
• Androgens enhance GH action.
• Oestrogens attenuate GH action.
• The oestrogen effect is route-dependent, occurring with oral delivery, which blunts the liver-mediated actions of GH by directly inhibiting GH receptor signalling.

Oral oestrogen delivery specifically blunts GH action through inhibition of hepatic GH receptor signalling.

• The attenuation of GH action by oestrogens is route-dependent.
• Oral oestrogen delivery blunts the liver-mediated actions of GH.
• The mechanism involves directly inhibiting GH receptor signalling at the hepatic level.
• This route-dependency distinguishes oral from non-oral oestrogen administration in terms of GH responsiveness.

Recombinant GH technology made it possible to investigate GH physiology and conduct replacement therapy trials in adults.

• Prior to recombinant technology, sufficient GH supplies for adult physiological studies and therapeutic trials were not available.
• Recombinant technology enabled both investigations into the physiology of GH action and establishment of benefits of replacement therapy.
• Global experience spanning over 30 years has attested to the safety, efficacy, and benefits of replacement therapy for adults with GHD.