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Neuroendocrinology and Pituitary

MON-054 - Metabolic Signaling to Pituitary Gonadotropes is Critical for Pre-Ovulatory LH and FSH Surge Activity

Monday, June 15, 2026
9:00 AM - 2:00 PM CT
The hypothalamic-pituitary-gonadal (HPG) axis is highly sensitive to metabolic status; however, the mechanisms which link metabolism and reproduction have yet to be fully characterized. Previous studies have demonstrated that the adipokine hormone leptin is required for fertility. Leptin promotes targeted hypothalamic expression, ultimately stimulating gonadotropin-releasing hormone (GnRH) secretion. At the pituitary level, loss of leptin receptors results in severe subfertility, though specific mechanisms remain unknown. We hypothesize that gonadotrope leptin signaling is critical for maintaining pre-ovulatory gonadotropin surge activity. To investigate this, we generated gonadotrope-specific leptin receptor knockout mice (Leprflox/flox; Gnrhr-Cre, hereafter cKO). Serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels were measured in control and cKO animals at 0900 during each stage of the estrous cycle (proestrus (P), estrus (E), metestrus (M), diestrus (D)) and around expected pre-ovulatory LH and FSH surge timepoints (P2000, P2030, P2130, P2400, and E0400). Serum hormone levels were consistent between mutants and controls throughout most of the estrous cycle; however, LH was significantly decreased in cKOs during the pre-ovulatory LH surge (P2030; p< 0.05). Pituitary LH protein content was unchanged, suggesting that the blunted LH surge in cKOs may be driven by gonadotrope secretion failure rather than altered synthesis. Assessment of FSH activity revealed significantly decreased serum hormone and Fshb mRNA expression in cKO samples during the secondary rise in FSH on the morning of estrus (E0400; p< 0.05). Consistent with blunted pre-ovulatory surges, ovarian antral follicles and corpora lutea were significantly reduced in cKO animals (p < 0.01; p< 0.05). Together, these results indicate that leptin signaling in the gonadotrope is critical for mediating gonadotropin surge activity, resulting in suppression of ovarian follicle maturation and ovulation. To identify specific mechanisms of action, we performed single-cell RNA sequencing (scRNA-seq) on control and cKO pituitaries (P0900; n=6/genotype). Differential abundance analyses revealed significant downregulation of Fshb, common α subunit (Cga), and secretory pathway transcripts in cKO gonadotropes (Log2FC<-1.00; Adj. p< 0.001). Curiously, several secretory granule components, namely secretogranin II (Scg2), were also significantly downregulated in cKO lactotrope populations. Confirmatory studies provide additional evidence of a reciprocal paracrine relationship between pituitary gonadotropes and lactotropes. Overall, our data offer novel insight into the mechanisms underlying metabolic signaling control of the HPG axis.

*Unless otherwise noted, all abstracts presented at ENDO must not be released to the press or the public until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.*