PPARG regulates gonadotropin-releasing hormone signaling in LbetaT2 cells in vitro and pituitary gonadotroph function in vivo in mice.

Peroxisome proliferators-activated receptor gamma (PPARG) ligands improve insulin sensitivity in type 2 diabetes and polycystic ovarian syndrome (PCOS). Despite clinical studies showing normalization of pituitary responsiveness to gonadotropin-releasing hormone (GnRH) in patients with PCOS, the precise role of PPARG in regulating the hypothalamic-pituitary-gonadal axis remains unclear. In the present study, we tested the hypothesis that the PPARG agonist rosiglitazone has a direct effect on the pituitary. In mouse LbetaT2 immortalized gonadotrophs, rosiglitazone treatment inhibited GnRH stimulation of the stress kinases p38MAPK and MAPKs/JNKs, but did not alter activation of ERKs, both in the presence and absence of activin. Furthermore, p38MAPK signaling was critical for both Lhb and Fshb promoter activity, and rosiglitazone suppressed the GnRH-mediated induction of Lhb and Fshb mRNA. Depletion of PPARG using a lentivirally encoded short hairpin RNA abolishes the effect of rosiglitazone to suppress activation of JNKs and induction of the transcription factors EGR1 and FOS as well as the gonadotropin genes Lhb and Fshb. Lastly, we show conditional knockout of Pparg in pituitary gonadotrophs caused an increase in luteinizing hormone levels in female mice, a decrease in follicle-stimulating hormone in male mice, and a fertility defect characterized by reduced litter size. Taken together, our data support a direct role for PPARG in modulating pituitary function in vitro and in vivo.

Human fetal ovary development involves the spatiotemporal expression of p450c17 protein.

OBJECTIVE: The purpose of this research was to characterize the spatiotemporal expression of P450c17 in the human fetal ovary. DESIGN: P450c17 protein was visualized in sections of control and anencephalic ovaries using immunohistochemistry. SUBJECTS: Subjects included control (nonanencephalic) and anencephalic human fetal ovaries during the second and third trimesters. RESULTS: In second-trimester control ovaries, P450c17 was highly expressed in primary interstitial cells (PIC) located between the ovigerous cords near the cortical-medullary border where meiosis and primordial follicle formation were occurring. Morphometric analysis revealed a progressive decrease in the number of PIC during the second trimester, suggesting that PIC might have a finite lifetime. Between 25 and 32 wk, relatively few cells stained positive for P450c17; however, after 33 wk, P450c17 was strongly expressed in theca interstitial cells (TIC) bordering developing follicles. Surprisingly, the TIC appeared remarkably early during folliculogenesis, e.g. as early as the primary-to-secondary transition, and exhibited notable hyperplasia throughout preantral and early antral follicle growth. Owing to large numbers of developing preantral follicles, the third trimester was characterized by an increased abundance of P450c17-positive TIC. During this time period, P450c17 was strongly expressed in the hilus interstitial cells juxtaposed to the rete ovarii. Studies of ovaries of anencephalic fetuses revealed a similar spatiotemporal pattern of P450c17 expression in the PIC, TIC, and hilus interstitial cells, consistent with the possibility that pituitary hormones may not be involved in P450c17 expression in fetal ovaries. CONCLUSION: We identified three different classes of P450c17-expressing interstitial cells in the human fetal ovary, each having a different spatiotemporal pattern of P450c17 expression and, presumably, a different set of physiological functions.