Feminization imprinted by developmental growth hormone

Area of Science:

• Endocrinology
• Hepatology
• Pharmacology

Background:

• Sex-specific regulation of hepatic drug-metabolizing enzymes (cytochromes P450 or CYPs) is permanent in adult females.
• The role of hormonal imprinting in female mammalian development is not fully understood.
• Previous work identified early growth hormone (GH) exposure as critical for programming male-specific CYP enzyme masculinization.

Purpose of the Study:

• To investigate the role of early developmental GH exposure in programming female-specific hepatic CYP expression.
• To determine if early GH exposure imprints the permanent sex-dependent regulation of hepatic CYPs in females.
• To elucidate the differential regulation of specific CYP enzymes by adult GH profiles.

Main Methods:

• Newborn female rats had GH secretion selectively blocked.
• Some rats received concurrent GH replacement or GH-releasing factor.
• Adult CYP2C12, CYP2C7, CYP2C6, and CYP2E1 expression levels were measured in relation to GH profiles.

Main Results:

• Early GH exposure imprints the expression of female-specific CYP2C12 and CYP2C7, making them dependent on the adult feminine GH profile.
• Female-predominant CYP2C6 and CYP2E1 expression is inversely related to GH levels, suppressed by both feminine and masculine GH profiles.
• Blocking early GH secretion altered adult enzyme expression, which was partially restored with GH treatment.

Conclusions:

• Early developmental GH exposure permanently imprints the expression patterns of specific hepatic CYPs in female rats.
• This imprinting establishes a lifelong dependence of CYP2C12 and CYP2C7 on the adult feminine GH profile.
• The regulation of CYP2C6 and CYP2E1 in adult females does not appear to require GH imprinting, but is influenced by adult GH levels.