Hello Jaswinder,
I have very limited experience of structural analyses in Creo (and none with thermal simulations), but I can share a few links that you might find useful:
https://monarch.qucosa.de/api/qucosa%3A20268/attachment/ATT-0/
https://www.diva-portal.org/smash/get/diva2:1357237/FULLTEXT01.pdf
https://morethesis.unimore.it/theses/available/etd-11052019-102329/unrestricted/Tesi_Antonio_Rella.pdf
https://webthesis.biblio.polito.it/21490/1/tesi.pdf
The last one is unfortunately in Italian, but I hope Google Translate can help making it sufficiently understandable.
First, I would suggest searching on the web for some reports on "simple geometry" including thermal loadcases and trying to replicate them in Creo - ideally I would look for analyses performed with well-known CAE suites like Ansys or Altair... before starting with your specific geometry. This will help you understand if settings in Creo about mesh, loads, constraints, etc. are correct.
For your question on design iterations, I would suggest looking at "Behavioral modeling extension" (BMX), which allows to run multiple analyses iterating combinations of dimensions: if you set correctly the boundaries of this "study" you may get an optimized result for your loadcase. Always consider some suitable safety factors according to the reliability of material datasheets you're using. See this demo:
https://www.youtube.com/watch?v=OECpFEl0r2M
As for fatigue, there's a "Fatigue Advisor Extension" which you might have access depending on your Creo license. I have never used it, but you may find some information on PTC's website.
Best regards and good luck for your simulations!