OR01-08 Impact of Pituitary Gonadotrope-Specific Deletion of the Transcription Factors, Creb and Icer, on HPG Axis Function in Male Mice

Abstract Disclosure: C.G. Meireles: None. N. Boris: None. K. Hausken: None. V. Garza: None. S.A. Pereira: None. G.A. Stamatiades: None. H. Kim: None. R.S. Carroll: None. U.B. Kaiser: None. Background and Objective: Pulsatile hypothalamic GnRH release stimulates FSH and LH synthesis in pituitary gonadotropes in a frequency- and amplitude-dependent manner. Low vs. high GnRH pulse frequencies preferentially increase Fshb and Lhb expression, respectively, potentially via differential induction of transcription factors such as Creb and Icer. In vitro, Creb phosphorylation and Fshb expression are increased to a greater extent at low GnRH pulse frequencies; Icer, which attenuates GnRH stimulation of Fshb expression, is induced to a greater extent at higher GnRH pulse frequencies. The mechanisms driving differential responses to pulsatile GnRH in vivo have not yet been fully elucidated. We hypothesized that gonadotrope-specific deletion of Creb or Icer would influence gonadotropin regulation and, consequently, reproduction and fertility in male mice in vivo. Methods and Results: Two mouse models, with gonadotrope-specific deletion of Creb (CrebKO) or Icer (IcerKO) were generated by crossing GnrhrGRIC/+ mice with Creb1fl/fl or Icerfl/fl mice, respectively. Reproductive phenotypes and pituitary gonadotrope responses to GnRH stimulation and gonadectomy (GDX) were evaluated, compared to their respective controls. CrebKO and IcerKO males had normal pubertal development, with similar testicular morphology, age and body weight at preputial separation (PS), compared to controls. Both CrebKO and IcerKO mice were fertile, with normal times to siring their first litters and similar intervals between litters, compared to controls. CrebKO male mice produced fewer pups (p=0.03); in contrast, IcerKO male mice had similar litter sizes compared to controls, in fertility tests. Intact CrebKO and IcerKO mice had similar basal and GnRH-induced LH and FSH levels, compared to controls. Interestingly, two (p=0.0012) and seven (p=0.0001) days after GDX, CrebKO mice had higher serum LH levels, whereas IcerKO mice had lower serum LH levels 2 days after GDX (p=0.01), compared to controls. IcerKO mice had lower serum FSH levels post-GDX, whereas CrebKO mice had normal serum FSH levels post-GDX. IcerKO males had higher LH pulse frequency (p=0.04) but normal amplitude, while CrebKO male mice had similar frequency and amplitude, compared to controls. Conclusions: CrebKO male mice had fewer pups, but their pituitary response to GnRH-stimulated LH secretion and serum FSH levels remained normal compared to the control group. In contrast, IcerKO male mice exhibited higher LH pulse frequencies, although serum LH levels were normal after GDX, and their fertility was similar to that of controls. The differences in the contributions of Creb and Icer to gonadotropin regulation in vivo compared to in vitro findings may be due to compensatory mechanisms present in vivo, which are not yet fully understood. Presentation: Saturday, July 12, 2025