T.M. Yalcinkaya

Salpingotomy versus salpingectomy in women with tubal pregnancy (ESEP study): an open-label, multicentre, randomised controlled trial.

BACKGROUND Tubal ectopic pregnancy can be surgically treated by salpingectomy, in which the affected Fallopian tube is removed, or salpingotomy, in which the tube is preserved. Despite potentially increased risks of persistent trophoblast and repeat ectopic pregnancy, salpingotomy is often preferred over salpingectomy because the preservation of both tubes is assumed to offer favourable fertility prospects, although little evidence exists to support this assumption. We aimed to assess whether salpingotomy would improve rates of ongoing pregnancy by natural conception compared with salpingectomy. METHODS In this open-label, multicentre, international, randomised controlled trial, women aged 18 years and older with a laparoscopically confirmed tubal pregnancy and a healthy contralateral tube were randomly assigned via a central internet-based randomisation program to receive salpingotomy or salpingectomy. The primary outcome was ongoing pregnancy by natural conception. Differences in cumulative ongoing pregnancy rates were expressed as a fecundity rate ratio with 95% CI, calculated by Cox proportional-hazards analysis with a time horizon of 36 months. Secondary outcomes were persistent trophoblast and repeat ectopic pregnancy (expressed as relative risks [RRs] with 95% CIs) and ongoing pregnancy after ovulation induction, intrauterine insemination, or IVF. The researchers who collected data for fertility outcomes were masked to the assigned intervention, but patients and the investigators who analysed the data were not. All endpoints were analysed by intention to treat. We also did a (non-prespecified) meta-analysis that included the findings from the present trial. This trial is registered, number ISRCTN37002267. FINDINGS 446 women were randomly assigned between Sept 24, 2004, and Nov 29, 2011, with 215 allocated to salpingotomy and 231 to salpingectomy. Follow-up was discontinued on Feb 1, 2013. The cumulative ongoing pregnancy rate was 60·7% after salpingotomy and 56·2% after salpingectomy (fecundity rate ratio 1·06, 95% CI 0·81-1·38; log-rank p=0·678). Persistent trophoblast occurred more frequently in the salpingotomy group than in the salpingectomy group (14 [7%] vs 1 [<1%]; RR 15·0, 2·0-113·4). Repeat ectopic pregnancy occurred in 18 women (8%) in the salpingotomy group and 12 (5%) women in the salpingectomy group (RR 1·6, 0·8-3·3). The number of ongoing pregnancies after ovulation induction, intrauterine insemination, or IVF did not differ significantly between the groups. 43 (20%) women in the salpingotomy group were converted to salpingectomy during the initial surgery because of persistent tubal bleeding. Our meta-analysis, which included our own results and those of one other study, substantiated the results of the trial. INTERPRETATION In women with a tubal pregnancy and a healthy contralateral tube, salpingotomy does not significantly improve fertility prospects compared with salpingectomy. FUNDING Netherlands Organisation for Health Research and Development (ZonMW), Region Västra Götaland Health & Medical Care Committee.

Robotic-assisted laparoscopic ovarian tissue transplantation

OBJECTIVE To describe a technique for frozen-banked ovarian tissue transplantation using robotic-assisted laparoscopy. DESIGN Case study. SETTING Academic tertiary care center. PATIENT(S) A 38-year-old patient in remission for non-Hodgkin lymphoma, whose ovarian tissue had been frozen for 3 years. INTERVENTION(S) Robotic-assisted laparoscopic transplantation of thawed ovarian cortical tissue to the remaining ovary and peritoneum. MAIN OUTCOME MEASURE(S) Resumption of spontaneous menses, follicular development, and ovulation as demonstrated by ultrasound, and serum E(2) and P levels. RESULT(S) The patient experienced cyclic spontaneous menstruation 6 months after the transplantation. Ovulation was confirmed by ultrasound and serum E(2) and P levels at month 11 after surgery. CONCLUSION(S) Robotic-assisted laparoscopic surgery may be a good, minimally invasive alternative for the ovarian tissue transplantation procedure to restore ovarian function.

Successful conservative management of cervical ectopic pregnancy: a case series.

ObjectiveTo report our experience of conservative treatment in four patients with cervical ectopic pregnancy.DesignCase series.SettingAcademic medical center.PatientsFour women diagnosed with cervical ectopic pregnancy managed conservatively.Intervention(s)Systemic methotrexate alone or combined with subsequent uterine artery embolization (UAE).Main outcome measuresConservative management with decreased rate of serious complications.ResultsNo hysterectomies were needed. One patient required subsequent intervention, UAE.ConclusionConservative treatment of cervical pregnancy might be successful with careful follow up and subsequent conservative interventions.

Gap junction blockade induces apoptosis in human endometrial stromal cells.

One of the most dynamic adult human tissues is the endometrium. Through coordinated, cyclical proliferation, differentiation, leukocyte recruitment, apoptosis, and desquamation, the uterine lining is expanded and shed monthly, unless pregnancy is established. Errors in these steps potentially cause endometrial dysfunction, abnormal uterine bleeding, failed embryonic implantation, infertility, or endometrial carcinoma. Our prior studies showed that gap junctions comprised of Gap junction alpha‐1 (GJA1) protein, also known as connexin 43 (CX43), subunits are critical to endometrial stromal cell differentiation. The current studies were undertaken to explore the mechanism of endometrial dysfunction when gap junction intercellular communication (GJIC) is disrupted. Gap junction blockade by two distinct GJIC inhibitors, 18α‐glycyrrhetinic acid (AGA) and octanol (OcOH), suppressed proliferation and induced apoptosis in endometrial stromal cells, as manifested by reduced biomarkers of cell viability, increased TUNEL staining, caspase‐3 activation, sub‐G1 chromosomal DNA complement, as well as shortened telomere length. Unexpectedly, we also observed that the chemical inhibitors blocked CX43 gene expression. Moreover, when endometrial stromal cells were induced to undergo hormonal decidualization, following a 7‐day exposure to 10 nM 17β‐estradiol + 100 nM progesterone + 0.5 mM dibutyryl cAMP, characteristic epithelioid changes in cell shape and secretion of prolactin were blunted in the presence of AGA or OcOH, recapitulating effects of RNA interference of CX43. Our findings indicate that endometrial stromal cell proliferation and maintenance of decidualized endometrial function are GJIC‐dependent, and that disruption of gap junctions induces endometrial stromal cell apoptosis. These observations may have important implications for several common clinical endometrial pathologies. Mol. Reprod. Dev. 81: 666–675, 2014.

Scientific principles of regenerative medicine and their application in the female reproductive system

The goal of regenerative medicine is to repair, replace, or regenerate diseased tissues/organs in order to restore normal function. In this paper we will first discuss the general principle of regenerative medicine and the various techniques and approaches that have been used to replace or regenerate cells in diseased tissues and organs. Then, we will review different regenerative medicine approaches that have been used to treat specific diseased tissues and organs of the reproductive system in both animal and human experiments. It is clear from this article that regenerative medicine holds significant promise, and we hope that the review will serve as a platform for further development of regenerative medicine technologies for the treatment of inadequacies of the reproductive system.

Cost-effectiveness of salpingotomy and salpingectomy in women with tubal pregnancy (a randomized controlled trial)

STUDY QUESTION Is salpingotomy cost effective compared with salpingectomy in women with tubal pregnancy and a healthy contralateral tube? SUMMARY ANSWER Salpingotomy is not cost effective over salpingectomy as a surgical procedure for tubal pregnancy, as its costs are higher without a better ongoing pregnancy rate while risks of persistent trophoblast are higher. WHAT IS KNOWN ALREADY Women with a tubal pregnancy treated by salpingotomy or salpingectomy in the presence of a healthy contralateral tube have comparable ongoing pregnancy rates by natural conception. Salpingotomy bears the risk of persistent trophoblast necessitating additional medical or surgical treatment. Repeat ectopic pregnancy occurs slightly more often after salpingotomy compared with salpingectomy. Both consequences imply potentially higher costs after salpingotomy. STUDY DESIGN, SIZE, DURATION We performed an economic evaluation of salpingotomy compared with salpingectomy in an international multicentre randomized controlled trial in women with a tubal pregnancy and a healthy contralateral tube. Between 24 September 2004 and 29 November 2011, women were allocated to salpingotomy (n = 215) or salpingectomy (n = 231). Fertility follow-up was done up to 36 months post-operatively. PARTICIPANTS/MATERIALS, SETTINGS, METHODS We performed a cost-effectiveness analysis from a hospital perspective. We compared the direct medical costs of salpingotomy and salpingectomy until an ongoing pregnancy occurred by natural conception within a time horizon of 36 months. Direct medical costs included the surgical treatment of the initial tubal pregnancy, readmissions including reinterventions, treatment for persistent trophoblast and interventions for repeat ectopic pregnancy. The analysis was performed according to the intention-to-treat principle. MAIN RESULTS AND THE ROLE OF CHANCE Mean direct medical costs per woman in the salpingotomy group and in the salpingectomy group were €3319 versus €2958, respectively, with a mean difference of €361 (95% confidence interval €217 to €515). Salpingotomy resulted in a marginally higher ongoing pregnancy rate by natural conception compared with salpingectomy leading to an incremental cost-effectiveness ratio €40 982 (95% confidence interval -€130 319 to €145 491) per ongoing pregnancy. Since salpingotomy resulted in more additional treatments for persistent trophoblast and interventions for repeat ectopic pregnancy, the incremental cost-effectiveness ratio was not informative. LIMITATIONS, REASONS FOR CAUTION Costs of any subsequent IVF cycles were not included in this analysis. The analysis was limited to the perspective of the hospital. WIDER IMPLICATIONS OF THE FINDINGS However, a small treatment benefit of salpingotomy might be enough to cover the costs of subsequent IVF. This uncertainty should be incorporated in shared decision-making. Whether salpingotomy should be offered depends on societys willingness to pay for an additional child. STUDY FUNDING/COMPETING INTERESTS Netherlands Organisation for Health Research and Development, Region Västra Götaland Health & Medical Care Committee. TRIAL REGISTRATION NUMBER ISRCTN37002267.

Phylogenetic Comparisons Implicate Sex Hormone-Binding Globulin in “Masculinization” of the Female Spotted Hyena (Crocuta crocuta)

Exposures to sex steroids during fetal development are thought to contribute to the unique urogenital anatomy and social dominance of the female spotted hyena: overt phenotypes not shared by other hyenids (i.e. striped hyena, brown hyena, and aardwolf). Because both androgens and estrogens influence development of genitalia and behavior, and because plasma SHBG regulates their access to tissues, we compared the Shbg gene sequences, structures, and steroid-binding properties in the four extant hyenids. We found the hyenid Shbg genes (>95% identical) and mature protein sequences (98% identical) are highly conserved. As in other mammals, the hyenid SHBG all bind 5α-dihydrotestosterone with high affinity (K(d) = 0.62-1.47 nm), but they also bind estrone and dehydroepiandrosterone with similarly high affinity, and this unusual property was attributed to specific amino acids within their SHBG steroid-binding sites. Phylogenetic comparisons also indicated that the spotted hyena SHBG precursor uniquely lacks two leucine residues and has a L15W substitution within its secretion signal polypeptide, the reduced size and hydrophobicity of which markedly decreases the production of SHBG and may therefore explain why serum SHBG concentrations in male and female spotted hyenas are approximately five times lower than in other hyenids. This is important because low plasma SHBG concentrations in spotted hyenas will increase exposure to biologically active androgens and estrogen as well as to their precursors (dehydroepiandrosterone and estrone), which may contribute to the masculinized external genitalia of female spotted hyenas and to female social dominance over males.

Salpingotomy versus salpingectomy in women with tubal pregnancy (European surgery in ectopic pregnancy study): An open-label, multicenter, randomized controlled trial

The standard surgical procedure for treatment of tubal ectopic pregnancy is salpingectomy, in which the affected fallopian tube is removed. A feasible alternative intervention, salpingotomy, has been promoted since 1957. With this procedure, the pregnancy is removed while the affected tube is preserved. There are 2 risks associated with salpingotomy: a repeated ectopic pregnancy in the same tube and a persistent trophoblast requiring additional treatment. Despite these potential drawbacks, salpingotomy has been widely used and often preferred over salpingectomy because it has been assumed that preservation of both tubes increased the prospects for a future pregnancy. However, limited data support this assumption, and it remains unclear whether the potential benefits of salpingotomy outweigh the risks. The aim of this open-label, multicenter, randomized controlled trial was to determine whether salpingotomy improves rates of ongoing pregnancy by natural conception compared with salpingectomy. Participants were 18 years or older with a laparoscopically confirmed tubal pregnancy and a healthy contralateral tube. All had a desire for a future pregnancy. At surgery, they were randomly assigned to receive salpingotomy or salpingectomy. The primary study outcome was ongoing pregnancy by natural conception. Differences between groups in cumulative ongoing pregnancy rates were expressed as a fecundity rate ratio using Cox proportional hazards analysis with a time horizon of 36 months. Secondary study outcomes were persistent trophoblast, repeated ectopic pregnancy, ongoing pregnancy after ovulation induction, intrauterine insemination, and in vitro fertilization. Patients and investigators who analyzed the data were not masked to the assigned intervention, but researchers who collected data for fertility outcomes were unaware of treatment allocation. Data were analyzed according to the intention to treat. The investigators performed a (nonprespecified) meta-analysis that included the data from the present trial. A total of 446 women were randomly assigned to salpingotomy (n = 215) or salpingectomy (n = 231) between 2004 and 2011. The patients were followed until February 1, 2013. There was no significant difference between the groups in the cumulative ongoing pregnancy rate (60.7% after salpingotomy vs 56.2% after salpingectomy; the fecundity rate ratio was 1.06, with a 95% confidence interval [CI] of 0.81–1.38, log-rank P = 0.678.) Persistent trophoblast occurred significantly more frequently in the salpingotomy group (14 [7%] vs 1 [<1%]; relative risk, 15.0; 95% CI, 2.0–113). The risk for repeated ectopic pregnancy was not significantly increased after salpingotomy Copyright

Culdocentesis Followed by Saline Solution-Enhanced Ultrasonography: Technique for Evaluation of Suspected Ectopic Pregnancy

STUDY OBJECTIVE To evaluate the use of a technique consisting of culdocentesis followed by saline solution-enhanced pelvic ultrasonography in cases suspect for ectopic pregnancy in which an accurate diagnosis could not be made using routine transvaginal ultrasound. DESIGN Retrospective clinical study (Canadian Task Force classification III). SETTING Academic medical center. PATIENTS Twenty patients with an initial diagnosis of pregnancy of unknown location. INTERVENTIONS In 20 patients with symptoms of early pregnancy and serum quantitative human chorionic gonadotropin concentration, ectopic pregnancy could not be confirmed or ruled out. Transvaginal ultrasound-guided culdocentesis was performed, and 300 to 400 mL of normal saline solution was injected into the posterior cul-de-sac and pelvis. Transvaginal ultrasound was repeated with particular attention to the floating fallopian tubes MEASUREMENTS AND MAIN RESULTS Using this technique, a tubal pregnancy was visualized in 15 of 20 patients, and ectopic pregnancy was ruled out in 5 patients. In all patients, appropriate management was provided according to the final diagnosis, and consisted of either methotrexate, laparoscopic salpingostomy or salpingectomy, or expectant management in patients with abnormal intrauterine pregnancies. CONCLUSION Ultrasound-guided culdocentesis followed by saline solution-enhanced pelvic ultrasound can be considered as a diagnostic tool in patients with suspected ectopic pregnancy in whom other methods fail to demonstrate this diagnosis.