**Thanks**

*Hormone Therapy and Replacement in Cancer and Aging-Related Diseases*

with better patients' survival.

which investigated tumor grade and depth of myometrial invasion, and 5-year relative survival in postmenopausal endometrial cancer patients. In this analysis, ever use of any MHT entailed lower risks of having moderately and poorly differentiated tumors. The lowest OD for poorly differentiated tumors were seen for ever users of cyclically combined estrogen-progestin [OR = 0.23 (95% CI: 0.07–0.73)]. Ever users of any form of MHT, particularly medium potency MHT users, had significantly lower risks for tumors with deep myometrial invasion, and adjusted estimated relative excess HRs revealed significantly improved survival for ever users of any form of MHT [RER = 0.40 (95% CI: 0.16–0.97)]; in particular ever users of any form of oestrogens [RER = 0.38 (95% CI: 0.15–0.99)]. The authors' conclusions were that MHT ever used induces a more favorable tumor characteristics, less aggressive and

**3.2 Immunohistochemistry for hyperplasia and endometrial cancer risk on** 

Endometrium is a tissue with strong capacities of renewal/remodeling for cell proliferation/new tissue formation, differentiation, apoptosis, angiogenesis which are highly regulated by ovarian steroids, and various locally expressed gene products, and with the presence of regenerative endometrial stem cells with their special capacities, which are maintained in menopause. The role and qualities of endometrial stroma in EIN, and cancer progression are very important, and the mechanisms of E and P4 in promoting proliferation on one side, secretory activity and differention on the other side are connected to the steroid receptors presence, and to the transformation of endometrial transcriptome, because of gene or epigenetic changes by hypermethylation of DNA and histones, with overexpression or underexpression of genes that encodes the proteins necessary for successful proliferation, apoptosis, angiogenesis, and fight against endometrial epithelial glands and stroma atypia The reported "hyperplasia" and no endometrial cancer from **Table 3** is not sufficient for the outcome prediction for long time. Molecular genetic researches related to hereditary predisposition (as Lynch syndrome, and Cowden syndrome) and to epigenetic changes are now used for uterine structures too, and endometrial

There are histological biomarkers for endometrial transcriptome assessment: estrogen (ER), progesterone (PR) receptors, membrane estrogen and progesterone receptors, and their polymorphism; enzymes involved in E2 metabolism to E1, and other molecules as bcl-2, p53, PAX-2, PTEN, VGEF, and microRNA (miRNA) can help to make the differences in the outcome of each patient. The proliferative activity induced by estrogen increases the risk for errors in transcription (microsatellite instability, K-ras mutation, PTEN gene mutations), which are essential for carcinogenesis [128]. Microsatellite instability (MSI) is a condition manifested by damaged DNA because of defects in normal DNA repair process; it induces progression of hyperplasia with atypia to endometrioid endometrial carcinoma—reported to be

Estrogen may operate through "classical" genomic pathways (*via* nuclear ERs) or non-genomic pathways (ERs in plasma membrane/cytoplasm or other receptors/ adaptors). Approximately 10% of the patients with type 1 endometrial cancer show gene defects promoting carcinogenesis; one representative example is hereditary non-polyposis colon cancer (HNPCC), known as Lynch syndrome [129] when the

miRNAs are short (19–25 nucleotides) naturally-occurring, non-coding RNA molecules that base-pair with the 3′ untranslated region of target miRNAs. miRNAs have emerged as key regulators of gene expression, a single miRNA can target

20–45% in such cases, and 0–11% in type 2 endometrial carcinoma.

lifetime risk for endometrial cancer is 40–60% [130].

**MHT: endometrial transcriptome and biomarkers**

transcriptome is more and more understood.

**74**

I thank Romanian patients who trust on my recommendations regarding non oral routes for MHT, when the majority used the oral route.

*Hormone Therapy and Replacement in Cancer and Aging-Related Diseases*
