Ovarian stimulation and oocyte cryopreservation in females with cancer.

PURPOSE OF REVIEW: We reviewed the most recent developments including the safety and effectiveness data and success rates in individualized ovarian stimulation protocols for adult and postpubertal females with cancer. RECENT FINDINGS: In women with breast cancer, aromatase inhibitor- and tamoxifen-supplemented stimulation protocols increase the margin of safety by limiting estrogen exposure. The outcomes of ovarian stimulation appear similar between cancer and noncancer populations, even with the recently developed random-start protocols, which allow initiation of ovarian stimulation anytime during the menstrual cycle. Based on lower anti-Mullerian hormone levels and primordial follicle density, carriers of BRCA pathogenic variants ( BRCApv ) have decreased ovarian reserve in comparison to women without those variants and may lose larger portion of their ovarian reserve post chemotherapy. Oocyte cryopreservation is also emerging as a suitable fertility preservation approach for selected postpubertal girls as young as 12 years of age. SUMMARY: Individualized ovarian stimulation approaches combined with improvements in cryopreservation techniques increased the success and safety margin to preserve fertility with oocyte freezing. Women with BRCApv , on the other hand, may be at disadvantage as they have lower ovarian reserve and may lose larger portion of their ovarian reserve post chemotherapy compared to women who do not carry these variants.

Breast cancer treatment and ovarian function.

The aim of this study was to provide an update on ovarian function and the mechanisms of gonadal damage after exposure to chemotherapy in breast cancer survivors. The alkylating agents are toxic to both primordial and growing follicles. However, anti-metabolite drugs are more likely to destroy preantral and antral follicles. Younger patients are more likely to have a higher ovarian reserve, and therefore, more likely to retain some residual ovarian function after exposure to gonadotoxic regimens. However, there can be significant variability in ovarian reserve among patients of the same age. Furthermore, patients with critically diminished ovarian reserve may continue to menstruate regularly. Therefore age and menstrual status are not reliable indicators of good ovarian reserve and might give a false sense of security and result in an adverse outcome if the patient is consulted without considering more reliable quantitative markers of ovarian reserve (antral follicle count and anti-Müllerian hormone) and fertility preservation is not pursued. In contrast to well-documented ovarian toxicity of older chemotherapy regimens, data for newer taxane-containing protocols have only accumulated in the last decade and data are still very limited regarding the impact of targeted therapies on ovarian function.

Oocyte cryopreservation with in vitro maturation for fertility preservation in girls at risk for ovarian insufficiency.

PURPOSE: To assess the feasibility and outcomes of oocyte cryopreservation with in vitro maturation (IVM) in post-pubertal girls undergoing fertility preservation (FP) for primary ovarian insufficiency (POI) risk. METHODS: Ovarian stimulation was performed with an antagonist protocol or progesterone priming. Ultrasound monitoring was performed transabdominally. Oocytes were retrieved transvaginally under IV sedation. Immature oocytes were subjected to IVM for up to 36 h. All MII oocytes were vitrified. The main outcome measure was the total number of mature oocytes cryopreserved. The secondary outcome was the increase in the mature oocyte yield after IVM. RESULTS: Indications for FP included mosaic Turner syndrome (mTS; n = 10), malignancy (n = 3), and POI risk (n = 2). The mean ± SD age, antral follicle count (AFC), and AMH levels were 14.2 ± 1.4 years, 8 ± 5.2 and 1.3 ± 1.3 ng/mL. In girls with mTS, the ovarian reserve was low for age (AFC 7.4 ± 4.7 and AMH 1.4 ± 1.6 ng/mL). Oocyte cryopreservation was possible in all girls with a range of 1-27 mature oocytes obtained, even in those who were previously exposed to chemotherapy or with low ovarian reserve, and no surgical complications were encountered. After IVM, the median mature oocyte yield increased significantly from 7.5 to 10.5 (p = 0.001). CONCLUSIONS: Oocyte cryopreservation appears to be feasible and safe in girls as young as 12 years of age at risk for POI The utility of IVM increases the yield of cryopreserved mature oocytes. Prior exposure to chemotherapy or low ovarian reserve should not be an automatic reason to exclude these girls from FP consideration.

Outcomes of random-start letrozole protocol with PGT-A in women with breast cancer undergoing fertility preservation.

PURPOSE  : To compare the cycle characteristics and outcomes of random-start-controlled ovarian stimulation (RSCOS) protocols to the outcomes of standard-start-controlled ovarian stimulation (SSCOS) cycles and to report the utility of PGT-A in these cycles. METHODS: One hundred and seventeen who underwent SSCOS and 39 who underwent RSCOS for oocyte and/or embryo cryopreservation before breast cancer chemotherapy were retrospectively evaluated. Mean number of embryos and blastocyst euploidy rates were the main outcome measures. RESULTS: A majority of RSCOS cycles were initiated in the luteal phase (66.6% luteal vs. 33.3% follicular). While the total dose of gonadotropins was significantly higher in the RSCOS (3720.8 ± 1230.0 vs. 2345.1 ± 803.6 IU; P < 0.001), the mean number of mature oocytes and embryos was similar to SSCOS. However, there was a trend for a higher number of mean embryos with luteal start RSCOS (6.9 ± 2.7 in late follicular start vs. 9.4 ± 4.2 in luteal start, P = 0.08). PGT-A was performed in 48% of the cases that underwent embryo cryopreservation in RSCOS (12 women, mean age = 35.3 ± 4.1; 87 blastocysts), revealing a euploidy rate of 36.2 ± 22.3% per patient. This rate was comparable to a 45% aneuploidy rate from similarly aged published data. Of the 7 RSCOS patients who returned for frozen embryo transfer, 5 delivered and one has an ongoing pregnancy, while in SSCOS, 18 out of 40 cycles resulted in live birth. CONCLUSION: Our data suggests that RSCOS fertility preservation cycle outcomes are similar to those with SSCOS and result in age-appropriate euploidy rates.

Autologous bone marrow-derived nucleated cell (aBMNC) transplantation improves endometrial function in patients with refractory Asherman's syndrome or with thin and dysfunctional endometrium.

PURPOSE: The purpose was to evaluate the effect of intrauterine injection of aBMNC on the endometrial function in patients with refractory Asherman's syndrome (AS) and/or thin and dysfunctional endometrium (TE). STUDY DESIGN: This is a prospective, experimental, non-controlled study MATERIAL AND METHODS: The study was carried out between December 2018 and December 2020 on 20 patients, who were of age < 45 years and had oligo/amenorrhea and primary infertility due to refractory AS and/or TE. One hundred ml BM was extracted. aBMNC cells were separated according to generic volume reduction protocol by using the Cell Separation System SEPAX S-100 table top centrifuge system. We have evaluated CD34+, mononuclear cell (MNC), and total nucleated cell (TNC) counts. The transplantation aBMNC was performed by two intrauterine injections at an interval of one week, transvaginally into the endometrial-myometrial junction by an ovum aspiration needle. Midcyclic endometrial thickness (ET) and gestations after transplantation were evaluated. RESULTS: The mean TNC, MNC, and CD34+ cells were 11.55 ± 4.7 × 108, 3.85 ± 2.01 × 108, and 7.00 ± 2.88 × 106 at first injection, respectively, and 6.85 ± 2.67 × 108, 2.04 ± 1.11 × 108, and 3.44 ± 1.31 × 106 at second injection, respectively. The maximum posttransplantation ET was significantly higher than the maximum pretransplantation ET: 2.97 ± 0.48 vs. 5.76 ± 1.19 (mean ± standard deviation, p < 0.01). Twelve patients had frozen-thaw embryo transfers after the study. In 42% (n = 5 of 12) of the patients, pregnancy was achieved. One of the five patients delivered a healthy baby at term. CONCLUSIONS: Autologous BMNC transplantation may contribute to endometrial function in patients with AS and/or TE.

Impact of adjuvant chemotherapy or tamoxifen-alone on the ovarian reserve of young women with breast cancer.

PURPOSE: To determine the longitudinal impact of adjuvant chemotherapy and tamoxifen-only treatments on the reproductive potential of women with breast cancer by using a sensitive ovarian reserve marker anti-Mullerian hormone (AMH) as a surrogate. METHODS: One-hundred-and-forty-two women with a primary diagnosis of breast cancer were prospectively followed with serum AMH assessments before the initiation, and 12, 18 and 24 months after the completion of adjuvant chemotherapy or the start of tamoxifen-only treatment. The chemotherapy regimens were classified into Anthracycline-Cyclophosphamide-based (AC-based) and Cyclophosphamide-Methotrexate + 5-Fluorouracil (CMF). Longitudinal data were analyzed by mixed effects model for treatment effects over time, adjusting for baseline age and BMI. RESULTS: Both chemotherapy regimens resulted in significant decline in ovarian reserve compared to the tamoxifen-only treatment (p < 0.0001 either regimen vs. tamoxifen for overall trend). AMH levels sharply declined at 12 months but did not show a significant recovery from 12 to 18 and 18 to 24 months after the completion of AC-based or CMF regimens. The degree of decline did not differ between the two chemotherapy groups (p = 0.53). In contrast, tamoxifen-only treatment did not significantly alter the age-adjusted serum AMH levels over the 24-month follow up. Likewise, the use of adjuvant tamoxifen following AC-based regimens did not affect AMH recovery. CONCLUSIONS: Both AC-based regimens and CMF significantly compromise ovarian reserve, without a recovery beyond 12 months post-chemotherapy. In contrast, tamoxifen-only treatment does not seem to alter ovarian reserve. These data indicate that the commonly used chemotherapy regimens but not the hormonal therapy compromise future reproductive potential.

Does pituitary suppression affect live birth rate in women with congenital hypogonadotrophic hypogonadism undergoing intra-cytoplasmic sperm injection? A multicenter cohort study.

In this retrospective multicenter cohort study, women with congenital hypogonadotrophic hypogonadism (CHH) (n = 57) who underwent intra-cytoplasmic sperm injection in-between 2010-2014 were compared to age-matched controls with tubal factor infertility (n = 114) to assess ovarian stimulation cycle and pregnancy outcomes. Live birth rates (LBRs) per started cycle were 31.6 and 24.6% in CHH and controls groups, respectively (p = 0.36). Comparable success rates were also confirmed with the logistic regression analysis (OR: 1.44, 95% CI: 0.78-2.67, p = 0.24). Of the 57 women with CHH, 19 were stimulated with the gonadotropin-releasing hormone (GnRH) antagonist protocol, 13 with the long-GnRH-agonist protocol. Pituitary suppression (PS) was not employed in the remaining 25 cases. Compared to women with PS, women without PS had significantly higher embryo implantation rates (21.6 versus 52.6%, p = 0.03). Although there was a trend favoring no PS, LBRs (25.0 versus 40.0%, p = 0.26) per cycle were short of statistical significance. LBRs per cycle (57.1 versus 31.2%, p = 0.11) and miscarriage rates (11.1 versus 16.7%, p = 0.75) were similar between CHH women who were given estrogen + progesterone and progesterone alone to support the luteal phase. In conclusion, the optimal stimulation protocol appears to be exogenous gonadotropin stimulation alone, without PS, and progesterone-only luteal phase support in CHH patients.

First pregnancies, live birth, and in vitro fertilization outcomes after transplantation of frozen-banked ovarian tissue with a human extracellular matrix scaffold using robot-assisted minimally invasive surgery.

BACKGROUND: Ovarian tissue cryopreservation is an experimental fertility preservation method and the transplantation techniques are still evolving. OBJECTIVE: We attempted to improve the technique with the utility of a human decellularized extracellular tissue matrix (ECTM) scaffold, robot-assisted minimally invasive surgery, and perioperative pharmacological support. STUDY DESIGN: We prospectively studied 2 subjects with hemophagocytic lymphohistiocytosis (patient A) and non-Hodgkin lymphoma (patient B) who underwent ovarian tissue cryopreservation at the age of 23 years, before receiving preconditioning chemotherapy for hematopoietic stem cell transplantation. Both experienced ovarian failure postchemotherapy and we transplanted ovarian cortical tissues to the contralateral menopausal ovary 7 and 12 years later, using a human ECTM scaffold and robotic assistance. The ECTM scaffold tissue compatibility was shown in preclinical studies. Patients also received estrogen supplementation and baby aspirin preoperatively to aid in the revascularization process. RESULTS: Ovarian follicle development was observed approximately 10 (patient A) and 8 (patient B) weeks after ovarian tissue transplantation. Following 8 and 7 cycles of in vitro fertilization, 9 and 10 day-3 embryos were cryopreserved (patients A and B, respectively). While the baseline follicle-stimulating hormone (range 3.6-15.4 mIU/mL) levels near normalized by 7 months and remained steady postovarian transplantation in patient A, patient B showed improved but elevated follicle-stimulating hormone levels throughout (range 21-31 mIU/mL). Highest follicle yield was achieved 14 (8 follicles; patient A) and 11 (6 follicles; patient B) months postintervention. Patient A experienced a chemical pregnancy after the third frozen embryo transfer attempt. She then conceived following her first fresh in vitro fertilization embryo transfer and the pregnancy is currently ongoing. Patient B conceived after the first frozen embryo transfer attempt and delivered a healthy girl at term. CONCLUSION: We report the first pregnancies after the minimally invasive transplantation of previously cryopreserved ovarian tissue with an ECTM scaffold. This approach seems to be associated with steady ovarian function after a follow-up of up to 2 years.

BRCA Mutations, DNA Repair Deficiency, and Ovarian Aging.

Oocyte aging has a significant impact on reproductive outcomes both quantitatively and qualitatively. However, the molecular mechanisms underlying the age-related decline in reproductive success have not been fully addressed. BRCA is known to be involved in homologous DNA recombination and plays an essential role in double-strand DNA break repair. Given the growing body of laboratory and clinical evidence, we performed a systematic review on the current understanding of the role of DNA repair in human reproduction. We find that BRCA mutations negatively affect ovarian reserve based on convincing evidence from in vitro and in vivo results and prospective studies. Because decline in the function of the intact gene occurs at an earlier age, women with BRCA1 mutations exhibit accelerated ovarian aging, unlike those with BRCA2 mutations. However, because of the still robust function of the intact allele in younger women and because of the masking of most severe cases by prophylactic oophorectomy or cancer, it is less likely one would see an effect of BRCA mutations on fertility until later in reproductive age. The impact of BRCA2 mutations on reproductive function may be less visible because of the delayed decline in the function of normal BRCA2 allele. BRCA1 function and ataxia-telangiectasia-mutated (ATM)-mediated DNA repair may also be important in the pathogenesis of age-induced increase in aneuploidy. BRCA1 is required for meiotic spindle assembly, and cohesion function between sister chromatids is also regulated by ATM family member proteins. Taken together, these findings strongly suggest the implication of BRCA and DNA repair malfunction in ovarian aging.

Lymphovascular space invasion and cervical stromal invasion are independent risk factors for nodal metastasis in endometrioid endometrial cancer.

AIMS: The purpose of this study was to investigate the potential roles of pathological variables in the prediction of nodal metastasis in women with endometrioid endometrial cancer (EC). MATERIALS AND METHODS: Women who underwent surgery for endometrioid EC between 1995 and 2012 were retrospectively reviewed. Those who underwent prior neoadjuvant chemotherapy or radiotherapy and inadequate lymphadenectomy as well as those with nonendometrioid histology, synchronous cancers, International Federation of Gynecology and Obstetrics stage IV disease, gross uterine serosal and/or gross adnexal involvement were excluded. Lymph node dissemination was defined as occurring in the following circumstances: (i) when nodal metastasis with pelvic and/or para-aortic (P/PA) lymph node dissection (LND) was performed or (ii) when there was recurrence in the P/PA lymph nodes after a negative LND or when LND was not performed. Univariate and multivariate logistic regression models were used to identify the pathological predictors of lymphatic dissemination. RESULTS: A total of 827 women with endometrioid EC were assessed; 516 (62.4%) of whom underwent P/PA LND and 205 (24.8%) underwent P LND. Sixty-seven (13%) women in the P/PA LND group and 5 (2.4%) in the P LND group had positive lymph nodes. Multivariate analysis confirmed cervical stromal invasion (OR 4.04, 95% CI 2.02-8.07 (P < 0.001)) and lymphovascular space invasion (LVSI) (OR 110.18, 95% CI 38.43-315.87 (P < 0.001)) as independent predictors of lymphatic dissemination. CONCLUSION: Cervical stromal invasion and LVSI are highly associated with LN metastasis. These markers may serve as a surrogate for nodal metastasis.

Does neoadjuvant chemotherapy plus cytoreductive surgery improve survival rates in patients with advanced epithelial ovarian cancer compared with cytoreductive surgery alone?

PURPOSE: The purpose of this study was to compare the outcomes of interval debulking surgery after neoadjuvant chemotherapy (NAC/IDS) with primary debulking surgery (PDS) in patients diagnosed with advanced epithelial ovarian cancer (EOC). METHODS: A total of 292 patients with IIIC and IV disease stages, who were treated with either NAC/IDS or PDS between 1995 and 2012 were retrospectively reviewed. The study population was divided into two groups: the NAC/IDS group (N=84) and the PDS group (N=208). Progression-free survival (PFS), overall survival (OS), and optimal cytoreduction were compared. RESULTS: The mean patient age was significantly higher in the NAC/IDS group (61.5±11.5 vs 57.8±11.1, p=0.01). Optimal cytoreduction was achieved in 34.5% (29/84) of the patients in the NAC/IDS group and in 32.2% (69/208) in the PDS group (p=0.825). The survival rates were comparable. The survival rate of patients who received optimal cytoreductive surgery in either the PDS or the NAC/IDS arm was significantly higher than that of patients who received suboptimal cytoreductive surgery (p<0.01 and p<0.01, respectively). Multivariate analysis confirmed the treatment method, amount of ascitic fluid, and optimal cytoreduction as independent factors for OS. CONCLUSIONS: There was no definitive evidence regarding whether NAC/IDS increases survival rates compared with PDS. NAC should be reserved for patients who cannot tolerate PDS or when optimal cytoreduction is not feasible.

Does neoadjuvant chemotherapy plus cytoreductive surgery improve survival rates in patients with advanced epithelial ovarian cancer compared with cytoreductive surgery alone?

PURPOSE: To compare the outcomes of interval debulking surgery (IDS) after neoadjuvant chemotherapy (NAC/IDS) with primary debulking surgery (PDS) in patients diagnosed with advanced epithelial ovarian cancer (EOC). METHODS: A total of 292 patients with stages IIIC and IV disease who were treated with either NAC/IDS or PDS between 1995 and 2012 were retrospectively reviewed. The study population was divided into two groups: the NAC/IDS group (N=84) and the PDS group (N=208). Progression-free survival (PFS), overall survival (OS), and optimal cytoreduction were compared. RESULTS: The mean age was significantly higher in the NAC/IDS group (61.5±11.5 vs 57.8±11.1 years, p=0.01). Optimal cytoreduction was achieved in 34.5% (29/84) of the patients in the NAC/IDS group and in 32.2% (69/208) in the PDS group (p=0.825). The survival rates were comparable. The mean survival rate of patients who achieved optimal cytoreductive surgery in either the PDS or the NAC/IDS arm was significantly higher than that of patients who achieved suboptimal cytoreductive surgery (p<0.001 and p<0.001, respectively). Multivariate analysis confirmed the treatment method, amount of ascitic fluid, and optimal cytoreduction as independent factors for OS. CONCLUSIONS: No definitive evidence was noticed regarding whether NAC/IDS increases survival compared with PDS. NAC should be reserved for patients who cannot tolerate PDS or when optimal cytoreduction is not feasible.

Benefits of short-term structured exercise in non-overweight women with polycystic ovary syndrome: a prospective randomized controlled study.

[Purpose] The short-term effects of structured exercise on the anthropometric, cardiovascular, and metabolic parameters of non-overweight women diagnosed with polycystic ovary syndrome were evaluated. [Subjects and Methods] Thirty women with a diagnosis of polycystic ovary syndrome were prospectively randomized to either a control group (n=16) or a training group (n=14) for a period of 8 weeks. Anthropometric, cardiovascular, and metabolic parameters and hormone levels were measured and compared before and after the intervention. [Results] Waist and hip measurements (anthropometric parameters); diastolic blood pressure; respiratory rate (cardiovascular parameters); levels of low-density lipoprotein cholesterol, total cholesterol, fasting glucose, and fasting insulin; and the homeostasis model assessment of insulin resistance index (metabolic parameters) were significantly lower in the training group after 8 weeks of exercise compared to the baseline values. After exercise, the training group had significantly higher oxygen consumption and high-density lipoprotein levels and significantly shorter menstrual cycle intervals. The corresponding values for controls did not significantly differ between the start and end of the 8-week experiment. [Conclusion] Short-term regular exercise programs can lead to improvements in anthropometric, cardiovascular, and metabolic parameters of non-overweight women with polycystic ovary syndrome.

Sphingosine-1-phosphate prevents chemotherapy-induced human primordial follicle death.

STUDY QUESTION: Can Sphingosine-1-phosphate (S1P), a ceramide-induced death pathway inhibitor, prevent cyclophosphamide (Cy) or doxorubicin (Doxo) induced apoptotic follicle death in human ovarian xenografts? SUMMARY ANSWER: S1P can block human apoptotic follicle death induced by both drugs, which have differing mechanisms of cytotoxicity. WHAT IS KNOWN ALREADY: S1P has been shown to decrease the impact of chemotherapy and radiation on germinal vesicle oocytes in animal studies but no human translational data exist. STUDY DESIGN, SIZE, DURATION: Experimental human ovarian xenografting to test the in vivo protective effect of S1P on primordial follicle survival in the chemotherapy setting. The data were validated by assessing the same protective effect in the ovaries of xenografted mice in parallel. PARTICIPANTS/MATERIALS, SETTING, METHODS: Xenografted mice were treated with Cy (75 mg/kg), Cy+S1P (200 µM), Doxo (10 mg/kg), Doxo+S1P or vehicle only (Control). S1P was administered via continuous infusion using a mini-osmotic pump beginning 24 h prior to and ending 72 h post-chemotherapy. Grafts were then recovered and stained with anti-caspase 3 antibody for the detection of apoptosis in primordial follicles. The percentage of apoptotic to total primordial follicles was calculated in each group. MAIN RESULTS AND THE ROLE OF CHANCE: Both Cy and Doxo resulted in a significant increase in apoptotic follicle death in human ovarian xenografts compared with controls (62.0 ± 3.9% versus 25.7 ± 7.4%, P < 0.01 and 76.7 ± 7.4% versus 25.7 ± 7.4%, P < 0.01, respectively). This chemotherapy-induced apoptotic death was reduced both in the Cy+S1P (32.7 ± 4.4%, P < 0.01) and the Doxo+S1P group (27.1 ± 7.6%, P < 0.01) compared with Cy and Doxo groups, respectively. In the Doxo+S1P and Cy+S1P groups, the percentages of apoptotic follicles were similar to those of vehicle-treated controls (P > 0.05). The findings from the ovaries of the severe combined immunodeficient mice mirrored the findings with human tissue. LIMITATIONS, REASONS FOR CAUTION: The functionality of the rescued human ovarian follicles needs to be evaluated in future studies though the studies in rodents showed that rescued oocytes can result in healthy offspring. In addition, the impact of S1P on cancer cells should be further studied. WIDER IMPLICATIONS OF THE FINDINGS: S1P and its future analogs hold promise for preserving fertility by pharmacological means for patients undergoing chemotherapy. STUDY FUNDING/COMPETING INTEREST(S): This research is supported by NIH's NICHD and NCI (5R01HD053112-06 and 5R21HD061259-02) and the Flemish Foundation for Scientific Research (FWO-Vlaanderen, grant number FWO G0.065.11N10). The authors have no conflicts of interest to disclose.

Triggering final oocyte maturation with gonadotropin-releasing hormone agonist (GnRHa) versus human chorionic gonadotropin (hCG) in breast cancer patients undergoing fertility preservation: an extended experience.

PURPOSE: To analyze the cycle outcomes and the incidence of ovarian hyperstimulation syndrome (OHSS), when oocyte maturation was triggered by gonadotropin-releasing hormone agonist (GnRHa) versus human chorionic gonadotropin (hCG) in breast cancer patients undergoing fertility preservation. METHODS: One hundred twenty-nine women aged ≤ 45 years, diagnosed with stage ≤ 3 breast cancer, with normal ovarian reserve who desired fertility preservation were included in the retrospective cohort study. Ovarian stimulation was achieved utilizing letrozole and gonadotropins. Oocyte maturation was triggered with GnRHa or hCG. Baseline AMH levels, number of oocytes, maturation and fertilization rates, number of embryos, and the incidence of OHSS was recorded. RESULTS: The serum AMH levels were similar between GnRHa and hCG groups (2.7 ± 1.9 vs. 2.1 ± 1.8; p = 0.327). There was one case of mild or moderate OHSS in the GnRHa group compared to 12 in the hCG group (2.1 % vs. 14.4 %, p = 0.032). The maturation and fertilization rates, and the number of cryopreserved embryos were significantly higher in the GnRHa group. CONCLUSIONS: GnRHa trigger improved cycle outcomes as evidenced by the number of mature oocytes and cryopreserved embryos, while significantly reducing the risk of OHSS in breast cancer patients undergoing fertility preservation.

Patients with gynecological malignancies are similar to other IVF patients without cancer for clinical and molecular reproductive parameters and DNA damage response pattern.

This study intended to investigate if gynecological cancers compromise ovarian function and reduce the success of assisted reproduction techniques (ART). No clinical and molecular data together is available on this issue for gynecological or other organ cancers. Steroidogenic pathways and DNA damage response characteristics of the granulosa cells retrieved from the 39 gynecological cancer patients were analyzed together with their clinical ART characteristics in comparison to 31 control ART patients. Patients with gynecological malignancies were similar to the control IVF patients for the number of mature oocytes retrieved, fertilization rates and embryo development competency. Molecular analyses of the granulosa cells retrieved from these cancer patients did not detect any perturbations in gonadotropin receptor expression and response, sex steroid production, cholesterol utilization/storage and, DNA damage response pattern in comparison to control IVF patients without cancer. This study provides the first reassuring clinical and molecular combined data set that the presence of gynecological malignancy does not appear to have any detrimental effect on clinical IVF cycle characteristics and ovarian functioning at molecular level.

The effect of long-term nicotine exposure on bone mineral density and oxidative stress in female Swiss Albino rats.

PURPOSE: To evaluate the effect of long-term low or high-dose nicotine exposure on bone mass via measuring bone mineral density (BMD) and oxidant-antioxidant status markers. METHODS: Thirty-five female Swiss Albino rats weighing 70 ± 10 g were divided as the control group (n = 12), low-dose nicotine group (n = 12) and high-dose nicotine group (n = 11). While the control group was given only normal drinking water, the low-dose nicotine group had 0.4 mg/kg per day and the high-dose nicotine group, 6.0 mg/kg per day of nicotine added to their water for the period of 1 year. BMD was determined with X-ray absorptiometry of lumbar vertebra, corpus femoris, proximal and distal femur. To evaluate oxidant-antioxidant status malondialdehyde (MDA) levels, superoxide dismutase (SOD) and catalase (CAT) activities were determined. RESULTS: When comparing the nicotine groups and controls, neither BMD nor oxidant-antioxidant status markers showed any statistically significant difference. In comparison to the controls, 12 months of high-dose oral nicotine exposure did not have a significant effect on BMD and low-dose nicotine exposure led to a statistically insignificant increase in BMD. CONCLUSIONS: Contrary to common belief, the results of this study show that nicotine is not responsible for the decrease in BMD leading to osteoporosis frequently seen in smokers. However, there is a need to explore the other harmful materials in tobacco which may be responsible for the alterations seen in BMD of smokers.

The association of RANK gene C421T and C575T polymorphisms with bone mineral density in postmenopausal Turkish women.

PURPOSE: To investigate the association between C421T polymorphism within exon 4, C575T polymorphism within exon 6 of the RANK gene and bone mineral density (BMD) variations in postmenopausal Turkish women. METHODS: One hundred seventy-eight postmenopausal women (patients = 100 and controls = 78) who applied to Ege University Faculty of Medicine, Department of Physical Medicine and Rehabilitation, for osteoporosis examination were analyzed. BMDs of the lumbar spine and femoral sites were measured. Patient and control groups were established based on their T-score values being above and/or below -1. After venous blood sampling, C421T and C575T polymorphisms of the RANK gene were assessed through PCR process following DNA extraction. RESULTS: Genotype frequencies for the C421T and C575T polymorphisms were compared between the control group and the patient group. No significant difference was detected between the two groups for both polymorphisms. There was also no significant difference between the control and patient groups in terms of the combined genotype (p = 0.752) and the combined haplotype analysis of the C421T and C575T polymorphisms (p = 0.723). In the control and patient groups separately, no significant differences in BMD values either at the femoral sites or at the lumbar spine were detected between the combined genotypes of the two polymorphisms. CONCLUSIONS: The genotypes, combined genotypes and allele frequencies of C421T and C575T polymorphisms of the RANK gene have not been found to be associated with BMD in Turkish women. Further studies including both sexes and more cases are required.

Assessment of total placenta previa by magnetic resonance imaging and ultrasonography to detect placenta accreta and its variants.

OBJECTIVE: To evaluate the importance of ultrasonography (US) and magnetic resonance imaging (MRI) in detecting placental adherence defects. MATERIAL AND METHODS: Patients diagnozed with total placenta previa (n = 40) in whom hysterectomy was performed due to placental adherence defects (n = 20) or in whom the placenta detached spontaneously after a Cesarean delivery (n = 20) were included into the study between June 2008 and January 2011, at the Department of Obstetrics and Gynecology Ege University (lzmir Turkey). Gray-scale US was used to check for any placental lacunae, sub-placental sonolucent spaces or a placental mass invading the vesicouterine plane and bladder Intra-placental lacunar turbulent blood flow and an increase in vascularization in the vesicouterine plane were evaluated with color Doppler mode. Subsequently all patients had MRI and the results were compared with the histopathologic examinations. RESULTS: The sensitivity of MRI for diagnosis of placental adherence defects before the operation was 95%, with a specificity of 95%. In the presence of at least one diagnostic criterion, the sensitivity and specificity of US were 87.5% and 100% respectively, while the sensitivity of color Doppler US was 62.5% with a specificity of 100%. CONCLUSIONS: Currently MRI appears to be the gold standard for the diagnosis of placenta accreta. None of the ultrasonographic criteria is solely sufficient to diagnose placental adherence defects, however they assist in the diagnostic process.

Evaluation of Intrafollicular Syndecan 1, Glypican 3, and Spermidine Levels in Women with Diminished Ovarian Reserve.

We aimed to evaluate the levels of Spermidine, Syndecan 1, and Glypican 3 (GPC3) in the follicle fluid of women with diminished ovarian reserve (DOR) and to examine the relationship of these markers with the number of embryos and clinical pregnancy. A total of 27 women with DOR and 34 women with normal ovarian reserve who underwent in vitro fertilization procedure were included in this prospectively designed study. Spermidine, Syndecan 1, and GPC3 levels were studied in the follicle fluid samples taken from the women at the time of oocyte retrieval by ELISA method, and their relations with the cycle outcomes were examined. The mean age was found as 38.1 ± 7.4 years in the DOR group and 35.1 ± 5.2 years in the control group (p = 0.027). When adjusted for age and body mass index, while the median Spermidine level was significantly higher (p < 0.001), both Syndecan 1 (p < 0.001) and GPC3 (p = 0.006) were significantly lower in the DOR group compared with control group. The cut-off value of Spermidine for clinical pregnancy prediction was found as 74.08 ng/mL with 78.9% sensitivity and 57.1% specificity [OR: 5 (95% CI: 1.4-17.6); AUC: 0.621; p = 0.138], while it was 0.96 ng/mL with 84.2% sensitivity and 59.5% specificity [OR: 7.8 (95% CI: 2-31.1); AUC: 0.701; p = 0.004] for GP3 and 1.15 ng/mL with 78.9 sensitivity and 57.1% specificity [OR: 5 (95% CI: 1.4-17.6); AUC: 0.680; p = 0.009] for Syndecan 1. Intrafollicular spermidine, Syndecan 1, and GPC3 levels may have a role in ovarian aging. Further randomized controlled studies in a larger population are needed for the relationship of these markers with cycle and pregnancy outcomes.