Ayse Seyhan

Prospective assessment of the impact of endometriomas and their removal on ovarian reserve and determinants of the rate of decline in ovarian reserve

STUDY QUESTION Do the presence of endometriomas and their laparoscopic excision lead to a decrease in ovarian reserve as assessed by serum anti-Müllerian hormone (AMH) levels? SUMMARY ANSWER Both the presence and excision of endometriomas cause a significant decrease in serum AMH levels, which is sustained 6 months after surgery. WHAT IS KNOWN ALREADY No previous comparison of serum AMH levels between women with and without endometrioma has been reported. However, studies have suggested a decline in serum AMH levels 1-3 months after endometrioma excision but long-term data are needed. STUDY DESIGN, SIZE, DURATION A prospective cohort study including 30 women with endometrioma >2 cm were age matched with 30 healthy women without ovarian cysts. PARTICIPANTS/MATERIALS, SETTING, METHODS Women with endometrioma underwent laparoscopic excision with the stripping technique. Serum AMH level and antral follicle count (AFC) were determined preoperatively, 1 and 6 months after surgery. Correlation analyses were undertaken in order to identify determinants of surgery-related change in ovarian reserve. MAIN RESULTS AND THE ROLE OF CHANCE Compared with controls at baseline, women with endometrioma had lower AMH levels (4.2 ± 2.3 versus 2.8 ± 2.2 ng/ml, respectively, P = 0.02) and AFC (14.7 ± 4.1 versus 9.7 ± 4.8, respectively, P < 0.01). Serum AMH levels were further decreased 6 months after surgery (2.8 ± 2.2 versus 1.8 ± 1.3 ng/ml, P = 0.02), while AFC remained unchanged (9.7 ± 4.8 versus 10.4 ± 4.2, P = 0.63). The rate of decline in AMH was not correlated with age, laterality of endometrioma, cyst diameter or the number of primordial follicles on the surgical specimens. The preoperative serum AMH level was positively correlated with the rate of decline in serum AMH after surgery (r = 0.47, P = 0.02). LIMITATIONS, REASONS FOR CAUTION The absence of a non-treated group of women with endometriomas as a further control prevents comment on the presence of a progressive decline in ovarian reserve related to endometrioma per se. The sample size may be too small for detection of factors correlated with the extent of ovarian damage. WIDER IMPLICATIONS OF THE FINDINGS While the findings are mostly in agreement with previous studies, the present study is the first to show that the presence of endometrioma per se is associated with a decrease in ovarian reserve. The extent of surgery-related decline in ovarian reserve is not predictable using preoperative or perioperative factors. It may be prudent to measure AMH levels preoperatively and delay/avoid surgical excision as far as is possible if subsequent fertility is a concern. Additional studies are required to further investigate whether the endometrioma-related decline in ovarian reserve per se is progressive in nature and whether it exceeds the surgery-related decline. STUDY FUNDING/COMPETING INTEREST(S) This study was funded by the Research Fund of the Uludag University School of Medicine. The authors have no conflict of interest associated with this study.

Severe early ovarian hyperstimulation syndrome following GnRH agonist trigger with the addition of 1500 IU hCG

STUDY QUESTION Is severe early ovarian hyperstimulation syndrome (OHSS) completely prevented with the GnRH agonist trigger and 1500 IU hCG luteal rescue protocol? SUMMARY ANSWER Severe early OHSS can occur even after the GnRH agonist trigger and 1500 IU hCG luteal rescue protocol. WHAT IS KNOWN ALREADY Prior studies including over 200 women who received the GnRH agonist trigger and 1500 hCG luteal rescue protocol have reported complete prevention of severe early OHSS. Only a few late OHSS cases have been reported and it has been suggested that this protocol can be safely applied to any women under risk. STUDY DESIGN, SIZE, DURATION This retrospective cohort study included all women who were at high risk of OHSS and were given the GnRH agonist trigger plus hCG luteal rescue protocol between December 2008 and August 2012 in the two participating centers. PARTICIPANTS/MATERIALS, SETTING, METHODS There were 23 women with a mean estradiol level of 4891 ± 2214 pg/ml and a mean number of >12 mm follicles of 20 ± 6 on the day of ovulation triggering. OHSS was categorized according to the Golan criteria. MAIN RESULTS AND THE ROLE OF CHANCE Overall 6 of the 23 (26%) women developed severe OHSS. Five women had severe early OHSS requiring ascites drainage and hospitalization and three of these women did not undergo embryo transfer. The number of follicles measuring 10-14 mm on the day of triggering was significantly different between women who developed severe early OHSS and those who did not. LIMITATIONS, REASONS FOR CAUTION The small number of women with severe early OHSS may have prevented identification of other significant risk factors. WIDER IMPLICATIONS OF THE FINDINGS Although the GnRH agonist plus 1500 IU hCG luteal rescue protocol significantly decreases the risk of severe OHSS, this life threatening complication can still occur in high-risk patients. It would be prudent to avoid hCG luteal rescue and freeze all embryos for future transfer in such women particularly when there are ≥18 follicles with 10-14 mm diameters even with few larger follicles.

High dose cabergoline in management of ovarian hyperstimulation syndrome

OBJECTIVE To describe a case of moderate ovarian hyperstimulation syndrome (OHSS) that was treated with high dose cabergoline. DESIGN Case report. SETTING Private assisted reproduction center. PATIENT(S) A 29-year-old woman who developed early moderate OHSS despite preventive cabergoline administration (0.5 mg/day) following controlled ovarian hyperstimulation for IVF treatment. INTERVENTION(S) Cabergoline dose was increased to 1 mg/day upon diagnosis of OHSS on the second day after oocyte collection and embryo transfer was postponed to the fifth day after oocyte collection. MAIN OUTCOME MEASURE(S) Resolution of OHSS and achievement of healthy live birth. RESULT(S) OHSS resolved rapidly despite occurrence of pregnancy and patient delivered a healthy boy at term. CONCLUSION(S) The higher cabergoline dose might have prevented an increase in the severity of OHSS and its prolongation following occurrence of pregnancy. Randomized controlled trials assessing the efficacy and safety of different doses and durations of cabergoline administration in both prophylactic and therapeutic settings are required.

Comparison of automated and manual follicle monitoring in an unrestricted population of 100 women undergoing controlled ovarian stimulation for IVF

BACKGROUND Ovarian response to gonadotrophin stimulation is monitored with serial ultrasound (US) examinations. Sonography-based Automated Volume Count (SonoAVC) is a relatively new three-dimensional (3D) US technology, which automatically generates a set of measurements including the mean follicular diameter (MFD) and a volume-based diameter (d(V)) for each follicle in the ovaries. The present study aimed to assess the applicability and reproducibility of this automated follicle measurement method in an IVF programme. METHODS For this prospective method comparison study, 100 women undergoing US monitoring of a controlled ovarian stimulation cycle were recruited. Each follicle was manually measured by taking the mean of maximal diameters on three orthogonal planes with two-dimensional (2D) US. A 3D volume of each ovary was then captured. The ovarian volumes were later analysed using SonoAVC. The agreement between the two methods for the numbers of follicles and the size of the leading follicle was assessed with the Bland-Altman method. The reproducibility of SonoAVC measurements was assessed with the intraclass correlation coefficient (ICC). RESULTS Both SonoAVC-generated MFD and d(V)-based follicle counts, as well as the leading follicle diameter, had good agreement with conventional 2D US measurements. SonoAVC measurements had very good reproducibility, with ICC ≥0.8 for most evaluations. CONCLUSIONS Automated follicle monitoring with SonoAVC can replace or be used interchangeably with conventional 2D measurements. Automated follicle monitoring can save time, provide a method of quality control and create opportunities for developing HCG criteria based on follicular volume or for monitoring patients from a distance.

Medical treatment of uterocutaneous fistula with gonadotropin-releasing hormone agonist administration.

BACKGROUND: Uterocutaneous fistula is a rare complication of uterine surgery. All published cases have been surgically treated with hysterectomy and excision of the fistulous tract. We report a case of uterocutaneous fistula that was successfully treated with gonadotropin-releasing hormone agonist administration. CASE: A 25-year-old woman reported bloody discharge during her periods from a previous Pfannenstiel incision. A fistulous tract leading from the incision scar to the uterus was diagnosed. Leuprolide acetate depot was administered twice subcutaneously at a dose of 11.25 mg. The fistulous tract closed spontaneously, and the patient was symptom free thereafter. CONCLUSION: Medical treatment with gonadotropin-releasing hormone agonists should be considered before resorting to surgery for treatment of uterocutaneous fistulae.

The Impact of Endometriosis and Its Treatment on Ovarian Reserve.

Endometriosis is a chronic disease mostly affecting women at reproductive age. There is a clear association between endometriosis and infertility; however, exact mechanisms are unknown. Some evidence suggests an adverse effect on oocytes. Endometriosis and its surgical treatment can affect quantitative ovarian reserve as well. In the presence of endometriomas, serum level of anti-Müllerian hormone (AMH) seems a more reliable marker of ovarian reserve than antral follicle count. Women with endometrioma have decreased serum AMH levels as compared with healthy controls. This is further declined after surgical excision, and the decline seems permanent. Bipolar cauterization of the ovary seems to be playing a role on ovarian damage. Extraovarian endometriosis and its surgical treatment can also be associated with decreased ovarian reserve, but there is limited information. Patients with endometriosis should be informed about fertility preservation options, especially in the presence of bilateral endometriomas or prior to surgery.

Prevention of adhesion formation following ovarian surgery in a standardized animal model: comparative study of Interceed and double layer Surgicell.

Aim:  Comparison of antiadhesive performances of double layer Surgicell and single layer Interceed following ovarian surgery in a rabbit model.

The role of corifollitropin alfa in controlled ovarian stimulation for IVF in combination with GnRH antagonist

Corifollitropin alfa is a synthetic recombinant follicle-stimulating hormone (rFSH) molecule containing a hybrid beta subunit, which provides a plasma half-life of ∼65 hours while maintaining its pharmocodynamic activity. A single injection of corifollitropin alfa can replace daily FSH injections for the first week of ovarian stimulation for in vitro fertilization. Stimulation can be continued with daily FSH injections if the need arises. To date, more than 2500 anticipated normoresponder women have participated in clinical trials with corifollitropin alfa. It is noteworthy that one-third of women did not require additional gonadotropin injections and reached human chorionic gonadotropin criterion on day 8. The optimal corifollitropin dose has been calculated to be 100 μg for women with a body weight ≤60 kg and 150 μg for women with a body weight >60 kg, respectively. Combination of corifollitropin with daily gonadotropin-releasing hormone antagonist injections starting on stimulation day 5 seems to yield similar or significantly higher numbers of oocytes and good quality embryos, as well as similar ongoing pregnancy rates compared with women stimulated with daily rFSH injections. Stimulation characteristics, embryology, and clinical outcomes seem consistent with repeated corifollitropin-stimulated assisted reproductive technologies cycles. Multiple pregnancy or ovarian hyperstimulation syndrome rates with corifollitropin were not increased over daily FSH regimen. The corifollitropin alfa molecule does not seem to be immunogenic and does not induce neutralizing antibody formation. Drug hypersensitivity and injection-site reactions are not increased. Incidence and nature of adverse events and serious adverse events are similar to daily FSH injections. Current trials do not provide information regarding use of corifollitropin alfa in anticipated hyper- and poor responders to gonadotropin stimulation. Although corifollitropin alfa is unlikely to be teratogenic, at the moment data on congenital malformations is missing.

Does the use of gonadotropin-releasing hormone antagonists in natural IVF cycles for poor responder patients cause more harm than benefit?

Abstract Poor ovarian response to controlled ovarian stimulation (COS) is one of the most critical factors that substantially limits the success of assisted reproduction techniques (ARTs). Natural and modified natural cycle IVF are two options that could be considered as a last resort. Blocking gonadotropin-releasing hormone (GnRH) actions in the endometrium via GnRH receptor antagonism may have a negative impact on endometrial receptivity. We analysed IVF outcomes in 142 natural (n = 30) or modified natural (n = 112) IVF cycles performed in 82 women retrospectively. A significantly lower proportion of natural cycles reached follicular aspiration compared to modified natural cycles (56.7% vs. 85.7%, p < 0.001). However, the difference between the numbers of IVF cycles ending in embryo transfer (26.7% vs. 44.6%) was not statistically significant between natural cycle and modified natural IVF cycles. Clinical pregnancy (6.7% vs. 7.1%) and live birth rates per initiated cycle (6.7% vs. 5.4%) were similar between the two groups. Notably, the implantation rate was slightly lower in modified natural cycles (16% vs. 25%, p > 0.05). There was a trend towards higher clinical pregnancy (25% vs. 16%) and live birth (25% vs. 12%) rates per embryo transfer in natural cycles compared to modified natural cycles, but the differences did not reach statistical significance.

Short and long term outcomes of children conceived with assisted reproductive technology

Despite their wide and global use, possible short and long-term effects of fertility treatments on children is not well-established. In this review, birth defects and perinatal complications and their relationship with assisted reproductive technology (ART), along with long-term effects of ART on cardiovascular system, metabolism, behavior, cognitive skills, and childhood cancers are discussed. Children conceived through ART are at increased risk for birth defects and perinatal complications such as preterm delivery, low birth weight and small for gestational age. Parental characteristics, underlying infertility etiology and ART procedures themselves may contribute to this. The long-term effects of ART are difficult to establish. Studies so far report that ART children have normal social, emotional, cognitive, and motor functions. Likewise, despite some minor inconsistencies in some studies, they do not seem to be at increased risk for childhood cancers. However, there are a number of studies that imply vascular system may be adversely affected by ART and its possible consequences should be further investigated with follow up studies. Large scale studies with long-term follow up periods are required to determine the effects of ART on conceived children.