User retention is much more important than number of ads.
It's actually shown that the longer an ad is there, the more likely it will be clicked.
You get payed per click not per number of ads.
Work with your advertisers to get ads relevant to your audience.
Changing and making ads pop up all the time is a bad idea.
As others have said, per layout, or on a change of game state is usually a better time to show or change an advertisement.