Developmental programming: impact of prenatal testosterone excess on pre- and postnatal gonadotropin regulation in sheep.
The goal of this study was to explore mechanisms that mediate hypersecretion of LH and progressive loss of cyclicity in female sheep exposed during fetal life to excess testosterone. Our working hypothesis was that prenatal testosterone excess, by its androgenic action, amplifies GnRH-induced LH (but not FSH) secretion and, thus, hypersecretion of LH in adulthood, and that this results from altered developmental gene expression of GnRH and estradiol (E2) receptors, gonadotropin subunits, and paracrine factors that differentially regulate LH and FSH synthesis. We observed that, relative to controls, females exposed during fetal life to excess testosterone, as well as the nor-aromatizable androgen dihydrotestosterone, exhibited enhanced LH but not FSH responses to intermittent delivery of GnRH boluses under conditions in which endogenous LH (GnRH) pulses were suppressed. Luteinizing hormone hypersecretion was more evident in adults than in prepubertal females, and it was associated with development of acyclicity. Measurement of pituitary mRNA concentrations revealed that prenatal testosterone excess induced developmental changes in gene expression of pituitary GnRH and E2 receptors and paracrine modulators of LH and FSH synthesis in a manner consistent with subsequent amplification of LH release. Together, this series of studies suggests that prenatal testosterone excess, by its androgenic action, amplifies GnRH-induced LH response, leading to LH hypersecretion and acyclicity in adulthood, and that this programming involves developmental changes in expression of pituitary genes involved in LH and FSH release.
Manikkam
Mohan
M
Department of Pediatrics, the Reproductive Sciences Program, and the Center for Statistical Consultation and Research, University of Michigan, Ann Arbor, Michigan 48109-0404, USA.
Thompson
Robert C
RC
Herkimer
Carol
C
Welch
Kathleen B
KB
Flak
Jonathan
J
Karsch
Fred J
FJ
Padmanabhan
Vasantha
V
D000818:Animals; D013196:Dihydrotestosterone / Q000008:administration & dosage / Q000031:analogs & derivatives; D030762:Estrous Cycle; D005260:Female; D005333:Fetus / Q000187:drug effects* / Q000502:physiology; D005640:Follicle Stimulating Hormone / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D007987:Gonadotropin-Releasing Hormone / Q000008:administration & dosage; D007273:Injections, Intramuscular; D007986:Luteinizing Hormone / Q000378:metabolism*; D010060:Ovulation / Q000502:physiology*; D010902:Pituitary Gland / Q000737:chemistry / Q000187:drug effects / Q000254:growth & development; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D011959:Receptors, Estradiol / Q000235:genetics; D011966:Receptors, LHRH / Q000235:genetics; D012741:Sexual Maturation; D012756:Sheep / Q000196:embryology* / Q000502:physiology; D013739:Testosterone / Q000008:administration & dosage*
D011959:Receptors, Estradiol; D011966:Receptors, LHRH; D013196:Dihydrotestosterone; D007987:Gonadotropin-Releasing Hormone; D013739:Testosterone; C030445:dihydrotestosterone propionate; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone