Developmental programming of polycystic ovary syndrome (PCOS): prenatal androgens establish pancreatic islet α/β cell ratio and subsequent insulin secretion.
Exogenous androgenic steroids applied to pregnant sheep programmes a PCOS-like phenotype in female offspring. Via ultrasound guidance we applied steroids directly to ovine fetuses at d62 and d82 of gestation, and examined fetal (day 90 gestation) and postnatal (11 months old) pancreatic structure and function. Of three classes of steroid agonists applied (androgen - Testosterone propionate (TP), estrogen - Diethystilbesterol (DES) and glucocorticoid - Dexamethasone (DEX)), only androgens (TP) caused altered pancreatic development. Beta cell numbers were significantly elevated in prenatally androgenised female fetuses (P = 0.03) (to approximately the higher numbers found in male fetuses), whereas alpha cell counts were unaffected, precipitating decreased alpha:beta cell ratios in the developing fetal pancreas (P = 0.001), sustained into adolescence (P = 0.0004). In adolescence basal insulin secretion was significantly higher in female offspring from androgen-excess pregnancies (P = 0.045), and an exaggerated, hyperinsulinaemic response to glucose challenge (P = 0.0007) observed, whereas prenatal DES or DEX treatment had no effects upon insulin secretion. Postnatal insulin secretion correlated with beta cell numbers (P = 0.03). We conclude that the pancreas is a primary locus of androgenic stimulation during development, giving rise to postnatal offspring whose pancreas secreted excess insulin due to excess beta cells in the presence of a normal number of alpha cells.
School of Life, Sport and Social Sciences, Edinburgh Napier University, Edinburgh EH11 4BN, UK.
S
S
Ramaswamy
School of Life, Sport and Social Sciences, Edinburgh Napier University, Edinburgh EH11 4BN, UK.
C
C
Grace
School of Life, Sport and Social Sciences, Edinburgh Napier University, Edinburgh EH11 4BN, UK.
A A
AA
Mattei
MRC Centre for Reproductive Health, The Queens Medical Research Institute, The University of Edinburgh, Edinburgh EH16 4TJ, UK.
K
K
Siemienowicz
School of Life, Sport and Social Sciences, Edinburgh Napier University, Edinburgh EH11 4BN, UK.
W
W
Brownlee
School of Life, Sport and Social Sciences, Edinburgh Napier University, Edinburgh EH11 4BN, UK.
J
J
MacCallum
MRC Centre for Reproductive Health, The Queens Medical Research Institute, The University of Edinburgh, Edinburgh EH16 4TJ, UK.
A S
AS
McNeilly
MRC Centre for Reproductive Health, The Queens Medical Research Institute, The University of Edinburgh, Edinburgh EH16 4TJ, UK.
W C
WC
Duncan
School of Life, Sport and Social Sciences, Edinburgh Napier University, Edinburgh EH11 4BN, UK.
M T
MT
Rae
D000728:Androgens / Q000502:physiology*; D000818:Animals; D047108:Embryonic Development; D005260:Female; D005951:Glucose Tolerance Test; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000166:cytology*; D008297:Male; D011085:Polycystic Ovary Syndrome / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D011247:Pregnancy; D012756:Sheep / Q000196:embryology*
D000728:Androgens; D007328:Insulin