Aydin Arici

HOXA10 is expressed in response to sex steroids at the time of implantation in the human endometrium.

Hox genes are well-known transcriptional regulators that play an essential role in directing embryonic development. Mice that are homozygous for a targeted disruption of the Hoxa10 gene exhibit uterine factor infertility. We have recently demonstrated that HOXA10 is expressed in the adult human uterus. To examine expression of HOXA10 during the menstrual cycle, Northern blot analysis and in situ hybridization were performed. Expression of HOXA10 dramatically increased during the midsecretory phase of the menstrual cycle, corresponding to the time of implantation and increase in circulating progesterone. Expression of HOXA10 in cultured endometrial cells was stimulated by estrogen or progesterone. Stimulation of HOXA10 by progesterone was concentration-dependent within the physiologic range, and the effect of estrogen was inhibited by cycloheximide. These results identify sex steroids as novel regulators of HOX gene expression. HOXA10 may have an important function in regulating endometrial development during the menstrual cycle and in establishing conditions necessary for implantation in the human.

Endometriosis and Infertility : Epidemiology and Evidence-based Treatments

Endometriosis is an estrogen‐dependent disorder defined as the presence of endometrial tissue outside of the uterine cavity. A leading cause of infertility, endometriosis has a prevalence of 0.5–5% in fertile and 25–40% in infertile women. The optimal choice of management for endometriosis‐associated infertility remains obscure. Removal or suppression of endometrial deposits by medical or surgical means constitutes the basis of endometriosis management. Current evidence indicates that suppressive medical treatment of endometriosis does not benefit fertility and should not be used for this indication alone. Surgery is probably efficacious for all stages of the disease. Controlled ovarian hyperstimulation with intrauterine insemination is recommended in early‐stage and surgically corrected endometriosis when pelvic anatomy is normal. In advanced cases, in vitro fertilization is a treatment of choice, and its success may be augmented with prolonged gonadotropin‐releasing hormone analog treatment. Further randomized clinical trials focusing on diverse etiopathogenic mechanisms and therapeutic innovation are necessary to find more conclusive, evidence‐based answers regarding this enigmatic disease.

Pathogenesis of endometriosis

Endometriosis is a common gynecologic disorder characterized by the presence of endometrial tissue outside the uterine cavity. Various theories have been put forth to explain the mechanisms for the development of this disease. Although no single theory can explain all cases of endometriosis, the retrograde menstruation theory has gained the widest acceptance. This theory proposes that viable endometrial tissue is refluxed through the fallopian tubes during menstruation and implants on peritoneal surface or pelvic organs. Retrograde menstruation occurs in 76% to 90% of women. The much lower prevalence of endometriosis suggests that additional factors determine susceptibility to endometriosis. Once in the peritoneal cavity, the survival and implantation of endometrial cells seem to be mediated by abnormal MMP and TIMP expression, altered immune milieu, aberrant local aromatase activity, and genetic and environmental factors.

Uterine Chemokines in Reproductive Physiology and Pathology

PROBLEM: Chemokines are increasingly recognized as important regulators of uterine function.

The effect of endometriosis on implantation : results from the Yale University in vitro fertilization and embryo transfer program

OBJECTIVE To investigate the effect of endometriosis on implantation. DESIGN Case-control study from Yale University IVF-ET program. PATIENTS Two hundred eighty-four consecutive IVF cycles were analyzed retrospectively. Patients with endometriosis only (n = 35; 89 cycles) were compared with an age-matched control group with tubal infertility (n = 70; 147 cycles) and also to a group with unexplained infertility (n = 15; 48 cycles). Data from the endometriosis group was analyzed further in subgroups of minimal-mild (43 cycles) and moderate-severe (46 cycles). RESULTS No difference was found in the number and the quality of oocytes retrieved and fertilization rates between the endometriosis, the tubal infertility, and the unexplained infertility groups. The quality and the number of embryos transferred in each group were comparable. A trend toward reduced pregnancy rate per transfer (14.8%) in the endometriosis versus tubal or unexplained infertility groups (25.7% and 23.3%, respectively) was observed. Implantation rate (gestational sac per transferred embryo) was significantly lower in the endometriosis versus the tubal infertility group (3.9% versus 8.1%; unexplained infertility group, 7.2%). Analysis of first cycles only across all groups revealed that the implantation rate also was significantly lower in the endometriosis versus the tubal infertility group (3.1% versus 9%; unexplained infertility group, 6.7%). Within the endometriosis group, although the pregnancy rate per cycle and per transfer were similar in subgroups, patients with minimal-mild endometriosis had the lowest implantation rate. CONCLUSION We conclude that, in patients with endometriosis, implantation rate is low. Abnormal implantation, which may be secondary to endometrial dysfunction or embryotoxic environment, is a factor in endometriosis-associated subfertility.

Immunology and endometriosis

Problem: Accumulating data suggests that aberrant immune responses during retrograde menstruation may be involved in the development of endometriosis.

Adverse effects of hydrosalpinx on pregnancy rates after in vitro fertilization- embryo transfer

OBJECTIVE To determine the effect of hydrosalpinx on the establishment of pregnancy after IVF-ET. DESIGN Metaanalysis. SETTING University medical center. PATIENT(S) AND INTERVENTION(S) All published reports (n=13) and abstracts (n=10) in English that examined the relation between hydrosalpinx and IVF-ET were included in the analysis. The metaanalysis was performed by first calculating the odds ratios for each trial and then combining them to obtain a pooled estimate of the odds ratio and a 95% confidence interval. MAIN OUTCOME MEASURE(S) Clinical pregnancy. RESULT(S) A total of 5,569 cycles was reviewed in the group without hydrosalpinx, and a total of 1,144 was reviewed in the group with hydrosalpinx. The clinical pregnancy rate was approximately 50% lower in patients who had hydrosalpinx. Similarly, the implantation rate was decreased by 50%. These effects were observed also in thawed ET cycles. The abortion rate was more than twofold higher in patients who had hydrosalpinx. CONCLUSION(S) This metaanalysis suggests that hydrosalpinx is associated with a reduced chance of implantation and an increased risk of pregnancy loss.

Transforming growth factor-β3 is expressed at high levels in leiomyoma where it stimulates fibronectin expression and cell proliferation

Abstract Objective: To investigate the expression of TGF-β3 in leiomyoma and myometrium as well as the effect of TGF-β3 on the expression of fibronectin and on the proliferation of leiomyoma and myometrial cells. Design: Observational and in vitro experimental study. Setting: University medical center. Patient(s): Women with (n = 18) leiomyoma. Intervention(s): First TGF-β3 mRNA and protein levels in myometrium and leiomyoma were measured, and then myometrial and leiomyoma cells in culture were treated with TGF-β3. Main Outcome Measure(s): TGF-β3 and fibronectin mRNA were evaluated by Northern analysis. Myometrial and leiomyoma cell proliferation was assessed with use of [ 3 H]thymidine incorporation. Result(s): The TGF-β3 mRNA level in the leiomyoma samples was 3.5-fold higher than in the myometrial samples. The highest TGF-β3 mRNA level was observed in leiomyoma samples from midsecretory phase and was 5-fold higher than in proliferative phase samples. Fibronectin mRNA expression also was higher in the leiomyoma than in the myometrium. TGF-β3 induced fibronectin expression in leiomyoma cells and directly stimulated myometrial and leiomyoma cell proliferation in cultures. Conclusion(s): These findings suggest that TGF-β3 may be mediating the growth-promoting effects of sex steroids on leiomyomas by playing a role in the fibrogenic process and cell proliferation that characterize these tumors.

Monocyte chemotactic protein-1 concentration in peritoneal fluid of women with endometriosis and its modulation of expression in mesothelial cells☆

OBJECTIVE To investigate monocyte chemotactic protein-1 concentrations in the peritoneal fluid (PF) of women with or without endometriosis, then assess peritoneal mesothelial cells as a potential source of monocyte chemotactic protein-1. DESIGN Prospective study. SETTING University medical center. PATIENT(S) Women with (n = 60) or without (n = 18) endometriosis. INTERVENTION(S) First monocyte chemotactic protein-1 levels in PF were measured, then mesothelial cells in culture were treated with cytokines. MAIN OUTCOME MEASURE(S) In PF and culture supernatants, monocyte chemotactic protein-1 was measured by ELISA. In vitro monocyte chemotactic protein-1 messenger RNA expression was evaluated by Northern analysis. RESULT(S) The median concentration of monocyte chemotactic protein-1 in PF of control women was 137 pg/mL (conversion factor to SI unit, 0.115; range, 12 to 418 pg/mL); that of women with moderate endometriosis was 205 pg/mL (range 65 to 6,000 pg/mL); and that of those with severe endometriosis was 1,165 pg/mL (0 to 2,602 pg/mL). Within the moderate to severe endometriosis group, monocyte chemotactic protein-1 levels were higher in women with untreated endometriosis (354 pg/mL range 0 to 6,000 pg/mL) than in women receiving GnRH agonist (128 pg/mL, range 0 to 216 pg/mL). In the control group, monocyte chemotactic protein-1 levels were higher in the proliferative phase than in the secretory phase. Mesothelial cells produced constitutively monocyte chemotactic protein-1; moreover, both interleukin-1 alpha and tumor necrosis factor-alpha induced higher levels of monocyte chemotactic protein-1. CONCLUSION(S) Levels of monocyte chemotactic protein-1 in PF were higher during the proliferative phase than secretory phase of control women and increased in moderate to severe endometriosis. The regulated expression of monocyte chemotactic protein-1 may recruit macrophages into PF and contribute to the pathogenesis of endometriosis.

Chemokines and human reproduction

OBJECTIVE To review the available information regarding chemotactic cytokines and their possible implications in human reproduction. DESIGN A thorough literature and MEDLINE search was conducted to identify studies relating to the role of chemokines in ovulation, menstruation, implantation, cervical ripening and preterm labor, and endometriosis. RESULT(S) Chemokines mediate leukocyte traffic through their specific receptors in various tissues. Although four families have been described to date, two remain the major subfamilies: alpha-chemokines (with interleukin-8 as representative for this group), and beta-chemokines (with monocyte chemotactic protein-1 as representative). Interleukin-8, monocyte chemotactic protein-1, and growth-regulated oncogene-alpha are involved in follicular development and atresia, ovulation, steroidogenesis, and corpus luteum function. Interleukin-8 showed cycle-dependent expression in human endometrium, and at the same time, stimulated endometrial stromal cell growth, acting as an autocrine growth factor. Interleukin-8 has been identified in human amnion, chorion, decidua, and villous placenta, and its level increases during labor. Levels of interleukin-8 correlate with the release of collagenases, a crucial step that regulates the process of cervical extracellular matrix remodeling. The levels of monocyte chemotactic protein-1; regulated on activation, normal T-expressed and secreted (RANTES); interleukin-8; and growth-regulated oncogene-alpha are elevated in the peritoneal fluid of women with endometriosis, and they correlate with the stage of the disease. CONCLUSION(S) Chemokines play a relevant role in many physiologic and pathologic situations, such as ovulation, menstruation, implantation, cervical ripening and preterm labor, and endometriosis. Their regulation soon may provide new therapeutic strategies.