Insights into the role of cervical mucus and vaginal pH in unexplained infertility / Sobre o papel do muco cervical e do PH vaginal na gênese da infertilidade inexplicada

Unexplained infertility diagnosis is made in the presence of a normal semen analysis when tubal patency and normal ovulatory function are established. Among several potential causes, unexplained infertility could be attributed to vaginal pH and cervical mucus abnormalities. Although the vaginal canal and the cervix generally function as effective barriers to sperm, and although the production of mucus is essential to transport them from the vagina to the uterine cavity, these factors receive little attention in the investigation of couples with unexplained infertility. A substantial reduction in sperm number occurs as they transverse the cervix. From an average of 200 to 300 million sperm deposited in the vagina, only a few hundred achieve proximity to the oocyte. Given this expected high spermatozoa loss, a slight modification in cervical mucus may rapidly transform the cervix into a "hostile" environment, which, together with changes in vaginal environment and cervix structure, may prevent natural conception and be a cause of infertility. In this review, we discuss the physiological role of the vaginal pH and cervical mucus in fertility, and describe several conditions that can render the cervical mucus hostile to sperm and therefore be implicated in the pathophysiology of unexplained infertility.

RESUMO O diagnóstico de infertilidade inexplicada baseia-se na presença de espermograma normal, constatadas também permeabilidade tubária e função ovulatória normais. Entre as várias causas potenciais de infertilidade inexplicada, a presença de muco cervical e pH vaginal anormais devem ser consideradas. Embora a produção adequada de muco cervical seja essencial para o transporte dos espermatozóides da vagina para a cavidade uterina, e tanto o canal vaginal quanto o colo do útero desempenham função importante como barreira à passagem dos espermatozóides, estes fatores recebem pouca atenção na investigação de casais com infertilidade inexplicada. Uma redução substancial do número de espermatozoides ocorre à medida que estes percorrem o trato reprodutivo feminino. Partindo de cerca de 200 a 300 milhões de espermatozoides depositados na vagina, apenas algumas centenas alcançam a proximidade do oócito. Alteracões do muco cervical podem rapidamente transformar o colo do útero num ambiente hostil, que em conjunto com alterações no ambiente vaginal e da estrutura de colo do útero, podem apresentar-se condicões impedientes para a concepção natural; desse modo, convertem-se em causa de infertilidade. Nesta revisão, discutimos o papel fisiológico do pH vaginal e do muco cervical na fertilidade, descrever várias condicões que podem tornar o muco cervical hostil aos espermatozoides e, por fim analisamos como estes fatores interferem na fisiopatologia da infertilidade inexplicada.

Immunohistochemical expression of estrogen and progesterone receptors in endometrial polyps: A comparison between benign and malignant polyps in postmenopausal patients.

The aim of the present study was to evaluate estrogen receptor (ER) and progesterone receptor (PR) expression in the glandular epithelium and stroma of benign and malignant endometrial polyps of postmenopausal patients. A total of 1,050 females underwent surgical hysteroscopy at the Professor Dr José Aristodemo Pinotti Women's Hospital, Center for Integral Attention to Women's Health of the State University of Campinas, between January 1998 and December 2008. Of the total number, 390 postmenopausal females with endometrial polyps were included in the study. Polypoid lesions were histologically classified as benign lesions (endometrial polyps and polyps with non-atypical simple hyperplasia or non-atypical complex hyperplasia) and premalignant and malignant lesions (polyps with atypical simple hyperplasia or atypical complex hyperplasia and carcinomatous polyps). ER and PR expression was evaluated by immunohistochemistry according to cell staining, intensity of nuclear staining and final score. The final score for receptor expression was compared between the benign and premalignant/malignant polyps. The prevalence of malignancy in endometrial polyps was 7.1% and was associated with postmenopausal bleeding. Only the final score for ER expression in the stroma of endometrial polyps was higher in the benign group than in the premalignant/malignant group, and this difference was significant. However, no difference was identified in PR expression. In addition, the risk of malignancy in endometrial polyps was significantly higher when the expression of ER and PR was negative in the stromal component of the polyp (P<0.01). The malignancy of endometrial polyps was also associated with a low expression of stromal ER, however, PR expression did not show any association with the risk of malignancy.

Gonadotropin therapy in assisted reproduction: an evolutionary perspective from biologics to biotech.

Gonadotropin therapy plays an integral role in ovarian stimulation for infertility treatments. Efforts have been made over the last century to improve gonadotropin preparations. Undoubtedly, current gonadotropins have better quality and safety profiles as well as clinical efficacy than earlier ones. A major achievement has been introducing recombinant technology in the manufacturing processes for follicle-stimulating hormone, luteinizing hormone, and human chorionic gonadotropin. Recombinant gonadotropins are purer than urine-derived gonadotropins, and incorporating vial filling by mass virtually eliminated batch-to-batch variations and enabled accurate dosing. Recombinant and fill-by-mass technologies have been the driving forces for launching of prefilled pen devices for more patient-friendly ovarian stimulation. The most recent developments include the fixed combination of follitropin alfa + lutropin alfa, long-acting FSH gonadotropin, and a new family of prefilled pen injector devices for administration of recombinant gonadotropins. The next step would be the production of orally bioactive molecules with selective follicle-stimulating hormone and luteinizing hormone activity.

Differences in estrogen and progesterone receptor expression in endometrial polyps and atrophic endometrium of postmenopausal women with and without exposure to tamoxifen.

Postmenopausal women who use tamoxifen present with an increased incidence of endometrial alterations, such as polyps and hyperplasia, in addition to a higher risk of malignant endometrial neoplasms. Among these endometrial changes, polyps are the most common, with a pathogenesis associated with hormonal influence. The objective of this study was to compare the expression of estrogen receptors (ERs) and progesterone receptors (PRs) in endometrial polyps from tamoxifen users with that in endometrial polyps and the atrophic endometrium of postmenopausal tamoxifen non-users. Among women undergoing surgical hysteroscopy, 84 tamoxifen users with benign endometrial polyps were selected. This group was compared to 84 samples of atrophic endometrium and to 252 benign polyps from postmenopausal women who were not treated with tamoxifen. The expression of ER/PR was assessed by immunohistochemical analysis, according to the percentage of stained cells, intensity of nuclear staining and final score. The polyps from tamoxifen users exhibited a higher expression of ER and PR in the glandular epithelium and stroma compared to the atrophic endometrium (P<0.0001). Compared to the polyps from women not treated with tamoxifen, tamoxifen users exhibited a higher PR expression in the epithelium (P=0.0014) and stroma (P=0.0056), with no difference in the expression of ER. In conclusion, endometrial polyps frequently exhibit an increase in ER expression, regardless of tamoxifen use. High levels of PR expression appear to be consistent with the estrogen agonist effects of tamoxifen.

Is the immunohistochemical expression of proliferation (Ki-67) and apoptosis (Bcl-2) markers and cyclooxigenase-2 (COX-2) related to carcinogenesis in postmenopausal endometrial polyps?

OBJECTIVE: To evaluate the pattern of Ki-67, Bcl-2 and COX-2 expression in the glandular epithelium and stroma of malignant and benign endometrial polyps in postmenopause. STUDY DESIGN: A total of 390 postmenopausal women underwent surgical hysteroscopy; women with endometrial polyps were included. Polypoid lesions were histologically classified as benign, premalignant or malignant lesions. Ki-67, Bcl-2 and COX-2 expression were evaluated by immunohistochemistry according to percentage of stained cells, staining intensity, and final score. RESULTS: The prevalence of malignancy in endometrial polyps was 7.1% and was associated with postmenopausal bleeding. The final score showed that only mean COX-2 expression was higher in malignant polyps both in the glandular epithelium (6.1 +/- 2.5) (p < 0.001) and stroma (2.4 +/- 3.0) (p < 0.01). There was a higher Bcl-2 expression, especially in the glandular epithelium, with no differences between benign polyps and premalignant/malignant polyps. Ki-67 expression was low in both benign polyps and premalignant/malignant polyps. CONCLUSION: Polyps in postmenopause have a high COX-2 expression that is higher in malignant polyps than in benign polyps. There was no difference in Ki-67 and Bcl-2 expression between malignant polyps and premalignant/malignant polyps.