Differential expression of functionality markers in mid-secretory endometrium of infertile women under treatment with ovulation-inducing agents.

OBJECTIVES: To analyze the expression of protein markers related to cell proliferation and death, as well as oestrogen and progesterone receptors in the endometrium of infertile women with hypothalamic-pituitary dysfunction treated with clomiphene citrate (CC) or recombinant follicle-stimulating hormone (rFSH), and compare them with ovulatory women. STUDY DESIGN: The study included 12 control ovulatory women and 29 anovulatory women, 19 of whom underwent ovulation induction with CC (n = 12) or rFSH (n = 5). Endometrial biopsies were obtained by Pipelle during the mid-secretory phase. Samples were stained with haematoxylin and eosin. Immunohistochemistry of proteins related to cell proliferation and cell death, as well as steroid receptors, was undertaken, and apoptosis was determined using TUNEL analysis. RESULTS: Immunohistochemical analysis of Ki67 expression showed significantly higher expression in the glandular epithelium of ovulatory women compared with the other groups. Glandular oestrogen receptor α expression was significantly lower in rFSH-treated women compared with ovulatory women. The number of apoptotic cells, Bax expression and progesterone receptor expression were similar in all groups. In contrast, Bcl-2 expression was significantly lower in the glandular epithelium of rFSH-treated women. CONCLUSIONS: In infertile women with hypothalamic-pituitary dysfunction, treatment with ovulation-inducing agents modifies the expression of proteins involved in cell proliferation and death, as well as the expression of steroid hormone receptors in the endometrium. These differences may help to explain, at the molecular level, the functionality of the endometrium during the implantation window, and may help to optimize pregnancy rates obtained with these treatments.

[Tumor suppressor gene p53: mechanisms of action in cell proliferation and death]. / El gen supresor de tumores p53: mecanismos de acción en la proliferación y muerte celular.

Normal development is a balance process, which includes proliferation and cell death. Indeed both proliferation and apoptotic cell death are very complex process that involves the participation of many genes. In both events, the tumor suppressor p53 is one of the most important and studied genes. This transcription factor activates several genes, which results in the arrest of the cellular cycle and cellular repair or apoptosis. Many are the signals that activate p53 function including: DNA damage by gamma or ultraviolet radiation and chemical agents and hypoxia, among others. When p53 is activated it can either induces the expression of p21 (Waf1, Cip-1), which participates in the cellular arrest between G1-S transition, or the expression of bax, PIGs, IGF-BP3, Fas, FasL and DR5. The former genes participate in the cascade of events that induce apoptosis. Cellular arrest or apoptosis depends of the degree of cellular damage. The final outcome of the different mechanisms of action of p53 is to maintain the genomic stability of the cell. Thus, the absence of this protein contributes to genomic instability, the accumulation of mutations and increased tumorigenesis. It has been demonstrated that p53 present mutations in 50-55% of all types of reported human cancer. These mutations are primary located in DNA binding domain of the protein, which results in the loss of its biological activity. Frequently, tumors that present wild type p53 have a better response towards therapy than those that present p53 mutations. This review is focused on the knowledge of the normal p53 cellular pathways and their alterations in cancer. It is clear that the understanding of p53 function in the development of this pathology may give new insights in future therapeutic strategies including gene therapy for cancer.

Variations of progesterone receptor and c-fos gene expression in the rat uterus after treatment with norethisterone and its A-ring reduced metabolites.

It has been suggested that some contraceptive derivatives of 19-nor-testosterone possess estrogenic activity that may facilitate the development of breast cancer. The aim of this work was to investigate the estrogenic properties of norethisterone (NET) and its A-ring-reduced derivatives by determining progesterone receptor (PR) and c-fos mRNA content of two estrogen-regulated genes in the uterus of ovariectomized rats. mRNA content was evaluated by Northern blot 1-6 h after 17 beta-estradiol administration. The highest PR and c-fos mRNA content was observed 3 h and 2 h after 17 beta-estradiol administration, respectively. NET did not modify either PR or c-fos mRNA content. In contrast, 5 alpha- and 3 beta, 5 alpha-NET significantly increased mRNA content of both genes. The increase in c-fos mRNA content induced by these reduced compounds was lower than that found with estradiol treatment. The overall results indicate that NET administration can indirectly induce estrogenic effects through the action of its 5 alpha-dihydro and 3 beta, 5 alpha-tetrahydro derivatives.