Isabelle P. Ryan

Ovarian steroid regulation of vascular endothelial growth factor in the human endometrium: implications for angiogenesis during the menstrual cycle and in the pathogenesis of endometriosis.

The human endometrium undergoes a complex process of vascular and glandular proliferation, differentiation, and regeneration with each menstrual cycle in preparation for implantation. Vascular endothelial growth factor (VEGF) is an endothelial cell-specific angiogenic protein that appears to play an important role in both physiological and pathological neovascularization. To investigate whether VEGF may regulate human endometrial angiogenesis, we examined VEGF messenger ribonucleic acid (mRNA) and protein throughout the menstrual cycle and studied the regulation of VEGF by reproductive steroids in isolated human endometrial cells. By ribonuclease protection analysis, VEGF mRNA increased relative to early proliferative phase expression by 1.6-,2.0-, and 3.6-fold in midproliferative, late proliferative, and secretory endometrium, respectively. In histological sections, VEGF mRNA and protein were localized focally in glandular epithelial cells and more diffusely in surrounding stroma, with greatest VEGF expression in secretory endometrium. Consistent with these in vivo results, the treatment of isolated human endometrial cells with estradiol (E2), medroxyprogesterone acetate (MPA), or E2 plus MPA significantly increased VEGF mRNA expression over the control value by 3.1-, 2.8-, and 4.7-fold, respectively. The VEGF response to E2 was rapid, with steady state levels of VEGF mRNA reaching 85% maximum 1 h after the addition of steroid. E2 also caused a 46% increase in secreted VEGF protein, and the combination of E2 and MPA caused an 18% increase. VEGF expression in endometriosis, an angiogenesis-dependent, estrogen-sensitive disease was similar to that seen in eutopic endometrium. Peritoneal fluid concentrations of VEGF were significantly higher in women with moderate to severe endometriosis than in women with minimal to mild endometriosis or no disease. VEGF, therefore, may be important in both physiological and pathological angiogenesis of human endometrium, as it is an estrogen-responsive angiogenic factor that varies throughout the menstrual cycle and is elevated in women with endometriosis.

Peritoneal fluid concentrations of the cytokine RANTES correlate with the severity of endometriosis

OBJECTIVE Endometriosis is a common gynecologic disorder in which the concentration and activation of peritoneal macrophages are increased. The goal of this study was to quantify pelvic fluid concentrations of two cytokines involved in macrophage recruitment and activation. STUDY DESIGN A case-control study of women undergoing pelvic surgery was conducted by collecting peritoneal fluid from 12 women without evidence of endometriosis (controls), 12 with mild, and 12 with moderate to severe endometriosis. Concentrations of RANTES and interferon gamma, soluble cytokines known to recruit and activate macrophages, were quantified by enzyme-linked immunosorbent assays. RESULTS Pelvic fluid concentrations of RANTES are elevated in women with endometriosis and the levels correlate with the severity of disease. By contrast, concentrations of interferon gamma appear unaffected by the presence of or severity of endometriosis. CONCLUSION The findings indicate that RANTES, a cytokine with potent chemotactic activity for human monocytes, may play an important role in the recruitment of peritoneal macrophages in endometriosis.

ENDOMETRIOSIS AND INFERTILITY : NEW CONCEPTS

Endometriosis is a common gynecological disorder with varied symptomatology including chronic pelvic pain, dysmenorrhea, and infertility. The association of endometriosis and infertility has been recognized for years, although definite evidence of causality still eludes us. In this review, we will explore three general concepts that enhance our understanding of the cellular and molecular interactions contributing to the pathophysiology of this disorder and that have steered current research in endometriosis. First, we review evidence of a local peritoneal inflammatory process, supported by the findings of elevated cytokine and growth factor concentrations in peritoneal fluid of affected patients. Second, we propose a role for angiogenic factors in the establishment of ectopic implants. Third, we review evidence for biochemical differences of eutopic and ectopic endometrium in endometriosis patients, which may contribute to both the pathogenesis and sequelae of this important disorder. Through information derived from these research efforts, we hope to develop better therapeutic interventions as adjunctive or alternative therapies to our current medical and surgical armamentarium.

Birth after intracytoplasmic sperm injection with use of testicular sperm from men with kartagener/immotile cilia syndrome

OBJECTIVE To describe two cases of in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) with testicular sperm in men with immotile cilia syndromes. DESIGN Case report. SETTING A university-based male infertility clinic and assisted reproduction unit. PATIENT(S) Two couples with male factor infertility due to Kartagener/immotile cilia syndrome. INTERVENTION(S) IVF/ICSI with testicular sperm. MAIN OUTCOME MEASURE(S) Semen characteristics, sperm viability, fertilization rate, and pregnancy. RESULT(S) With testicular sperm, the two pronuclear fertilization rates were 63% and 60% in two cases. One case resulted in the birth of normal healthy girl. CONCLUSION(S) With testicular sperm, successful oocyte fertilization after ICSI in couples with male Kartagener/immotile cilia syndrome is possible despite the lack of sperm motility.

Microglandular adenocarcinoma of the endometrium : A form of mucinous adenocarcinoma that may be confused with microglandular hyperplasia of the cervix

SummaryMicroglandular adenocarcinoma of the endometrium may cause diagnostic problems because of its bland cytologic appearance and its histologic similarity to benign microglandular hyperplasia of the cervix. We present two cases of microglandular adenocarcinoma and discuss the clinical, pathologic, and immunohistochemical findings. Both patients were postmenopausal women, one of whom was taking exogenous hormones. Endometrial biopsy specimens contained polypoid tissue fragments, within which were microcystic spaces lined by flattened, cuboidal, or columnar cells. Solid nests or sheets of tumor cells surrounded glands in some tissue fragments. The nuclei were uniform and bland, and mitotic figures, although readily identifiable, were infrequent (1 per 10 high-power fields). A majority of tumor cells contained intracytoplasmic mucin. Numerous neutrophils were present in gland lumens and tissues. Immunohistochemical stains for carcinoembryonic antigen and TAG72 (B72.3) revealed focal moderate to intense apical and cytoplasmic staining: immunostains for p53 protein were negative. One carcinoma was confined to the endometrium. whereas the other invaded into the inner one-third of the myometrium. Both patients were well after a limited follow-up of 1 year. Microglandular adenocarcinoma is a distinctive variant of endometrial carcinoma that is most likely a form of mucinous adenocarcinoma.

Outcomes of natural cycles versus programmed cycles for 1677 frozen-thawed embryo transfers

The study compares outcomes for patients with frozen embryos who had frozen-thawed embryo transfer (FET) timed to their natural ovulation cycle versus cycles in which endometrial timing was programmed with oestrogen and progesterone. A total of 1205 patients undergoing 1677 FET cycles between 1 January 2000 and 31 December 2006 were analysed. Comparisons were made for patients undergoing modified natural versus programmed FET cycles, as well as between patients using their own eggs for frozen embryos versus those using donor-egg-derived embryos. Clinical pregnancy (gestational sac on 7 week ultrasound) rates (CPR), as well as miscarriage rates, were significantly higher in programmed FET cycles in patients using their own eggs (106/262, 40.5% per embryo transfer, P = 0.015) However, there was not a difference in delivered pregnancies between cycle types in own egg patients (natural cycle delivery rate 245/862, 28.4%; programmed cycle delivery rate 77/262, 29.4%). Furthermore, CPR were not different in natural (38/129, 29.5%) versus programmed cycles (144/424, 34.0%) for ovum donor recipients, nor were delivered pregnancy rates different in natural (33/129, 25.6%) versus programmed cycles (114/424, 26.9%) for ovum donor recipients. In conclusion, there is no significant difference in delivery rates for FET in natural (278/991, 28.1%) versus programmed (191/686, 27.8%) cycles using both own embryos and donor-egg-derived embryos.