If you are using it for hunting, and or home defense, I recommend a revolver in a .357 with the ability to use .38 loads for low recoil practice. I keep +P hollow point-.38s for home defense.

The fact that you have already been shooting 22's up to .45's you have already covered the lightest to the big boy of carry guns. The thing that I tell everyone when it comes to handguns is that they require a lot of practice. That being said you need to get something that you can afford to shoot a lot. I switched from the .40S&W to the .45ACP and then to 9mm. I can afford to shoot a lot more 9mm than anything else but a .22. The choice of revolver or auto is up to you and what you like the best. There are +&- for both. I myself would push more toward an auto, the revolver for a couple of reasons, carry guns get dirty with everything, but dust, lint and gun oil is a big killer and revolvers are wide open for dirt and grime, Highcap Magazine vs six shooter, and unlike the earlier posts I believe autos are easier to use and operate.
My wife and I both Law Enforcement use and love Glocks, there are a lot to choose from but there is more Glocks used by Police than any other handgun. There is also a size Glock for everyone, in every caliber you can think of.
Now that is what I carry and advise anyone to carry, with a Kahr a close second.
Caliber is not as important with a handgun as hitting what you’re aiming a lot of times. I know this will ruffle feathers but people can look at the stats. If you were shot in the heart with a 9mm or a 45 you wouldn't know the difference.
TV cop shows and westerns have made it so that most people believe you just shoot everyone once and they just drop dead with a handgun. (of course there are exceptions) The truth is that more people die from wounds from a stabbing than pistol wounds.( Memphis Trauma Center) The handgun just don’t do enough damage.
What a Handgun is, is convenient, and concealable. I think of my handgun as something to fight my way to my rifle and or shotgun. But you can’t strap that to your leg or put it in your purse.
By all means carry a handgun when you’re out , but at home plan on the shotgun.
The most important thing of all is to get good self defense firearm training to learn how to fight with a handgun. Putting a paper plate at 25 yds and shooting at it might help you on a hog hunt, but it’s not really practical self-defense practice. Don’t be one of those people who buy a gun a box of practice ammo and a box of hollow points, and never learn to really use the gun, or handle it safely.
Check out FBI crime statistics they release them for every year.

It all depends on how you intend to carry it. If you want something you can carry in your purse, I suggest the Smith & Wesson 642, I believe it is. It has a shrouded hammer that won't catch on things in your purse as you pull it out and all you have to do is pull the trigger. I let my daughter shoot mine from the hip and she hit steel targets at 20+ feet easily. It doesn't kick a lot and there is no safety to worry about. It's point and shoot.

If you plan to use it at home only, I'd still recommend a revolver but perhaps a 357 magnum with lighter magnum loads. A semi-auto like a Glock is good if you practice and get use to it. If you don't have time to become proficient with it, go for the smaller 38 special.

My wife loves her North american 380

Ditto 007 on revolvers. Stay away from the autoloaders for a first handgun unless you decide on a .22 rimfire just for the fun of shooting a lot.

My wife was a deputy sheriff and ended up with a Colt Detective Special which she likes a lot. 2" barrel, but holds six rounds of .38 special.