**Abstract**

The Women's Health Initiative issues, confusions, and misunderstandings regarding women's and medical staff 's fears about coronary heart disease; stroke; venous thromboembolism; breast cancer; metabolic, cognitive and mood disorders; and general mortality have driven many attempts to promote other safe regimens for perimenopause/early menopause and midlife health. Perimenopause/early menopause climacteric syndrome may be safely treated with sequential transdermal/percutaneous estrogens and progestogens/vaginal progesterone or continuous transdermal estrogen plus intrauterine system medicated with progestogen/progesterone or with continuous combined transdermal estrogen-vaginal progesterone regimen, when menopause since 3 years. Endometrial safety is assessed in terms of endometrial hyperplasia and carcinoma prevention. Transvaginal sonography, hysteroscopy, and endometrial biopsy at 6/12 months ensure about secretory and atrophy/inactive endometrial aspects as markers for endometrial safety. The majority of endometrial carcinomas depicted after MHT are high grade, not estrogen dependent, developed on an atrophic endometrium. The histologic, genomic, and transcriptomic assessments with immunohistochemistry are diagnoses adjunct for cell proliferation/mitosis and apoptosis presence. Proteins, growth factors, cytokines as PAX2, PTEN and its genetic aberrations, microRNA-binding protein family (IMP, IGF-BP, progesterone dependent), bcl 2, Ki-67, K-ras, p53, p16, and steroid (estrogen and progesterone) receptors are markers for differentiation between benign hyperplasia/ endometrial intraepithelial neoplasia, type 1/type 2 endometrial carcinomas, and long-term outcome.

**Keywords:** non-oral routes, hormone therapy, perimenopause, menopause, endometrial hyperplasia, endometrial carcinoma
