I have a 27" (non-Retina) and progressives. Not a problem in my case (can't say whether I'm typical). Is your prescription designed to take computer usage into account?
I'm fairly tall, so with chair height adjusted in accordance with ergonomic practice (the iMac on a 27" high desk and at a bit less than arm's length with fingers extended - fist-bump distance), my eyes are about 23-24" from the display. That puts most of the display squarely in the computer-distance portion of the lenses. I have to tilt my head
down a bit if I need to read text at the very bottom of the display - it's already too distant for the book-reading portion of the prescription (which, for me, is about 12" from my eyes).
So if you have to use the bottom section of the lens to read the screen, you may be closer than is optimal for a display that size. At my book-reading distance the display fills most of my field of view (puts large sections of the screen outside of clear vision when wearing my glasses), and the keyboard is too close to type comfortably. Per
http://www.wikihow.com/Set-Up-an-Ergonomically-Correct-Workstation, if you have to tilt your head up, the display may be too high.
(FWIW, at least when you're my height, when a laptop's keyboard is at a comfortable height, the display is way too low -
that has given me a royal pain in the neck.)
I'm not certain why a 21.5" works better for you. I also use 21.5" iMacs extensively - the key for me is not display size, but the "desktop" size (more/less stuff on the screen). I spend a far greater amount of time mousing and moving windows about when the display is smaller (dot pitch being roughly the same on both displays).