Groups including GLAAD and DignityUSA have urged the Catholic leader to talk about the "institutionalized discrimination against LGBT people and families".
The letter describes how the teachings of the church and pastoral practices have resulted in a "compelling pastoral need" for "great healing and reconciliation."
The letter, supported by another 28 organisations and people, was sent to the Pope directly earlier in the month.
It reads: "Currently, our Church's teaching and pastoral practices surrounding LGBT people are causing enormous pastoral crisis, as well as upholding systematic, institutionalized discrimination against LGBT people and our families.
"In the U.S. and around the world, we are experiencing alienation from the Church, higher rates of poverty and violence, and discrimination in employment, housing, educational opportunities and access to health care."
The letter makes a plea for younger church-goers who lack support in the home, from school or from their faith communities: "This is a crisis that the church can help to address through effective pastoral care and programs that provides love and support for these youth."
Pope Francis will be visiting the US for five days towards the end of September.
