**3.2 Immunohistochemistry for hyperplasia and endometrial cancer risk on MHT: endometrial transcriptome and biomarkers**

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 transcriptome is more and more understood.

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

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

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

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*Endometrial Histology and Safety on Non-Oral Routes of Hormone Therapy...*

and potentially silence several hundred genes, and their involvement in aging by modulating the presence of steroid receptors, and other molecules in endometrial disorders, as are EIN, and both types of endometrial cancer. Recent studies have identified miRNAs regulated by estrogens in human endometrial stromal cells [131], fact discussed because E2 levels decline in postmenopause, and are various

Endometrial transcriptome analysis using techniques of immnohistochemistry may reveal women's risk to progesterone/progestin resistance and progression to EIN by measuring PRA and PRB; high expression of PRA and PRB suggesting decreased risk of persistence/progression to EIN, and the decrease of PRB is strongly associated to progression to EIN. No association was found with PTEN, and PTEN mutations, Pax-2, and Bcl-2, insulin like-growth factor II, with complex hyperplasia [132].

**4. Conclusions: future perspectives for middle aged women treated for** 

The discussed non-oral routes of MHT, meaning the transdermal/percutaneous route for estrogens, the vaginal route for micronized progesterone, and intrauterine system for proges-terone/progestogen are an update safe option for women with intact uterus, when the recommendation for MHT is during the "window of opportunity". The technology of obtaining these drugs/system will help medical staff and middle aged women to have a better quality of life, and less morbidity and mortality. The risk of endometrial proliferative lesions as hyperplasia and carcinoma is reduced in comparison to non-user women, and their prognosis is better comparative to non-users regarding tumor aggression and women's survival. Endometrial transcriptome and new biomarkers highlight priority areas for future research, such as increasing the diagnostic reproductibility of endometrial hyperplasia-benign, and EIN and to improve the discrimination between EIN and carcinoma, and identifying new biomarkers to stratify risks or serve as indicators of response to

I thank Romanian patients who trust on my recommendations regarding non

oral routes for MHT, when the majority used the oral route.

*DOI: http://dx.doi.org/10.5772/intechopen.89046*

age-associated disorders.

clinical treatment.

**Thanks**

**Conflict of interest**

Nothing to disclaim.

**perimenopausal symptoms**

*Endometrial Histology and Safety on Non-Oral Routes of Hormone Therapy... DOI: http://dx.doi.org/10.5772/intechopen.89046*

and potentially silence several hundred genes, and their involvement in aging by modulating the presence of steroid receptors, and other molecules in endometrial disorders, as are EIN, and both types of endometrial cancer. Recent studies have identified miRNAs regulated by estrogens in human endometrial stromal cells [131], fact discussed because E2 levels decline in postmenopause, and are various age-associated disorders.

Endometrial transcriptome analysis using techniques of immnohistochemistry may reveal women's risk to progesterone/progestin resistance and progression to EIN by measuring PRA and PRB; high expression of PRA and PRB suggesting decreased risk of persistence/progression to EIN, and the decrease of PRB is strongly associated to progression to EIN. No association was found with PTEN, and PTEN mutations, Pax-2, and Bcl-2, insulin like-growth factor II, with complex hyperplasia [132].
