In humans, early cortisol biosynthesis provides a mechanism to safeguard female sexual development.
In humans, sexual differentiation of the external genitalia is established at 7-12 weeks post conception (wpc). During this period, maintaining the appropriate intrauterine hormone environment is critical. In contrast to other species, this regulation extends to the human fetal adrenal cortex, as evidenced by the virilization that is associated with various forms of congenital adrenal hyperplasia. The mechanism underlying these clinical findings has remained elusive. Here we show that the human fetal adrenal cortex synthesized cortisol much earlier than previously documented, an effect associated with transient expression of the orphan nuclear receptor nerve growth factor IB-like (NGFI-B) and its regulatory target, the steroidogenic enzyme type 2 3beta-hydroxysteroid dehydrogenase (HSD3B2). This cortisol biosynthesis was maximal at 8-9 wpc under the regulation of ACTH. Negative feedback was apparent at the anterior pituitary corticotrophs. ACTH also stimulated the adrenal gland to secrete androstenedione and testosterone. In concert, these data promote a distinctive mechanism for normal human development whereby cortisol production, determined by transient NGFI-B and HSD3B2 expression, provides feedback at the anterior pituitary to modulate androgen biosynthesis and safeguard normal female sexual differentiation.
Human Genetics Division and Early Human Development and Stem Cells Group, University of Southampton, Southampton, United Kingdom.
Masahiro
M
Goto
Karen
K
Piper Hanley
Josep
J
Marcos
Peter J
PJ
Wood
Sarah
S
Wright
Anthony D
AD
Postle
Iain T
IT
Cameron
J Ian
JI
Mason
David I
DI
Wilson
Neil A
NA
Hanley
D015096:3-Hydroxysteroid Dehydrogenases / Q000235:genetics / Q000378:metabolism; D000302:Adrenal Cortex / Q000196:embryology / Q000378:metabolism; D000728:Androgens / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D005865:Gestational Age; D006801:Humans; D006854:Hydrocortisone / Q000096:biosynthesis* / Q000378:metabolism; D008954:Models, Biological; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D010903:Pituitary Gland, Anterior / Q000196:embryology / Q000254:growth & development / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism; D011987:Receptors, Steroid / Q000235:genetics / Q000378:metabolism; D012733:Sex Differentiation; D046468:Sexual Development / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
D000728:Androgens; D004268:DNA-Binding Proteins; C539821:NR4A1 protein, human; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D014157:Transcription Factors; D015096:3-Hydroxysteroid Dehydrogenases; D006854:Hydrocortisone