I have done this issue to death in many forums and with the assistance of one or two developers as well. There seems to be no real acknowledgement of this issue and certainly no solution, but if you continue searching you'll find it goes way back to DNN 2. In any case, I believe I have discovered the culprit, but again, have not had anyone confirm or deny it. I'll post my comments in here in the hope that someone in the core might finally pick up on it one day.
I am reasonably convinced that auto-completion of hidden password fields is causing the problem. I was never able to save an installation once it had happened. I installed perhaps 3 dozen times all up trying to trace it. I believe that having either the MSN toolbar form filler or turned on or clicking yes to certain Firefox password change warnings will cause it.
Since my last install, I have religiously turned off any toolbars prior to entering any of the settings pages in DNN, particular the site settings. Firefox gives a vital clue when it asks "which password do you want changed" or "do you want this password updated" on some pages even though I have not updated or changed anything like a password. Since doing this, I have not had the problem any more. As far as I'm concerened this is the cause.
The thing that continues to worry me on this growing multiportal installation of mine is if one of my clients triggers the problem via their sub portal. I back up my site folders and the database every day now just in case. It's far too much work to lose because of this silly issue. It'd cost me months of lost work.... scarey stuff really.
So.. reinstall from scratch, turn off all form fillers and see if that works for you.... and please report any results back here.
Good luck,
Rob