Yes, it's an interesting one. Most people will tell you that as Vagifem is such a low dose, it doesn't enter the blood stream once the vaginal tissues are plumped up. I didn't get breast tenderness when I started treatment for VA. However, I restarted systemic HRT a few weeks later, at the age of 67, after being taken off it 13 years earlier. I was given Tibolone at first, which gives a very low dose of oestrogen, and I did experience breast tenderness for the first few weeks. I am now on 3 pumps Oestrogel with no problems. I think it depends on how well you absorb these things, and how long your oestrogen receptors have been "asleep".
As to anxiety and insomnia, these certainly are associated with menopause. Systemic HRT would probably help in the first instance, then any remaining symptoms could be sorted out separately.
JP x