Abstract
Abstract Disclosure: B.V. Azevedo: None. N. Trigueiro: None. J.M. Marques: None. V. Yariwake: None. L. Tamashiro: None. R. Cruz: None. M.M. Veras: None. L. Carvalho: None. Introduction: The Ames lineage, a mouse model with a mutation in the Prop1 gene, exhibits GH, TSH, and PRL deficiencies along with low levels of gonadotropins. This has prompted an investigation into aging and reproductive restoration after hormone replacement reported in the literature. Aims: The present study aims to analyze the pathophysiologic mechanisms in the reproductive system and fertility restoration. Methods: This is a prospective study approved by the ethical committee for animal use at the University of Sao Paulo Medical School. An isogenic Ames lineage was categorized into four groups: 1) Ames wild-type mice, 2) untreated Ames dwarf mice with sexual maturity, 3) untreated Ames dwarf mice without sexual maturity, and 4) Ames dwarf mice under hormonal treatment. Male Ames dwarf mice received treatment with levothyroxine and human recombinant GH, starting at 30 days postnatal (dp) for 40 days, followed by weekly applications until 90 dp. At the time of euthanasia, a set of analyses were conducted on animals from each group to characterize sexual maturation, fertility, and tissue collection for reproductive parameter analyses, such as seminiferous tubule morphology by histology, testicular weight, gonadosomatic index, and spermogram analysis. Additionally, pituitary RNAseq was performed using the poly-A tail capture method with the Illumina stranded mRNA prep kit and sequenced on the NextSeq 2000. Results: Treated dwarf mice exhibited fertility restoration, an increase in testicular volume with an improvement of testicular function, and complete spermatogenesis. Untreated Ames dwarf mice were infertile, but those that reached sexual maturity without hormonal replacement showed improvements in reproductive parameters, such as enhanced testicular development, maturation of some seminiferous tubules, increased testicular weight, and improvement in the spermogram compared to immature Ames dwarf mice. Transcriptome analyses revealed distinct patterns of all Ames dwarf mice groups and the wild-type. It was observed a decrease in Fshb expression in the group without sexual maturation compared to the wild-type group. Additionally, Prl and Slc6a12 were upregulated in the spontaneously sexually mature Ames dwarf compared to the non-restored Ames dwarf mice. Conclusion: GH and levothyroxine treatment in the Ames lineage are effective in restoring fertility and improving reproductive parameters in male Ames dwarf mice. However, sexually mature Ames dwarf mice without treatment presented improvements in reproductive and molecular parameters despite remaining infertile. These findings provide valuable insights into the complex interaction among hormonal replacement, modulating mechanisms, and sexual maturity. Presentation: 6/2/2024
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