One major pinch point is Slade Lane Jn a few miles south of Manchester.
Leaving Manchester Piccadilly lines are paired by speed Up Fast - Down Fast - Up Slow - Down Slow.
At Slade Lane Jn they change to being paired by direction Up Slow - Up Fast - Down Fast - Down Slow.
This was changed to the current arrangement in 1960, prior to then the lines continued paired by direction all the way to Manchester London Road, so DS/DF/UF/US from west to east just continued all the way to London Road station.
There was a more recent proposal, which was apparently taken seriously for a while, to alter the lines between Adswood Road (the southern end of the four-track railway between Stockport and Cheadle Hulme) and Slade Lane to be paired by use to match the changed Piccadilly-Slade Lane layout. This would have made stopping trains at Levenshulme and Heaton Chapel use the up fast which would have been silly, and would have messed up interchange at Stockport to the detriment of passengers. Fortunately the idea eventually got killed.
Attached are before/after diagrams from the 1960 changes from "Britain's New Railway, O.S.Nock, Ian Allan 1966”.
I always feel the problems caused by the current layout at Slade Lane Junction are overstated, it seems to work well generally and seems to work better today than it used to in the 1970s in my experience. Yes, it's a constraint, but it was done for a reason and it seems to deliver on that.
EDIT My guess, from a passenger perspective based on the relatively large number of times I used to be stopped on a train wanting to pass through Slade Lane Junction in the 1970s compared with today when I rarely find that I am stopped is that the operating improvement came when London Road signal box was replaced by Manchester Piccadilly PSB in October 1988. For whatever reasons, the more modern box seems better suited to operate the layout.