Installing oncofertility programs for breast cancer in limited versus optimum resource settings: Empirical data from 39 surveyed centers in Repro-Can-OPEN Study Part I & II.

PURPOSE: As a further step to elucidate the actual diverse spectrum of oncofertility practices for breast cancer around the globe, we present and discuss the comparisons of oncofertility practices for breast cancer in limited versus optimum resource settings based on data collected in the Repro-Can-OPEN Study Part I & II. METHODS: We surveyed 39 oncofertility centers including 14 in limited resource settings from Africa, Asia & Latin America (Repro-Can-OPEN Study Part I), and 25 in optimum resource settings from the United States, Europe, Australia and Japan (Repro-Can-OPEN Study Part II). Survey questions covered the availability of fertility preservation and restoration options offered to young female patients with breast cancer as well as the degree of utilization. RESULTS: In the Repro-Can-OPEN Study Part I & II, responses for breast cancer and calculated oncofertility scores showed the following characteristics: (1) higher oncofertility scores in optimum resource settings than in limited resource settings especially for established options, (2) frequent utilization of egg freezing, embryo freezing, ovarian tissue freezing, GnRH analogs, and fractionation of chemo- and radiotherapy, (3) promising utilization of oocyte in vitro maturation (IVM), (4) rare utilization of neoadjuvant cytoprotective pharmacotherapy, artificial ovary, and stem cells reproductive technology as they are still in preclinical or early clinical research settings, (5) recognition that technical and ethical concerns should be considered when offering advanced and innovative oncofertility options. CONCLUSIONS: We presented a plausible oncofertility best practice model to guide oncofertility teams in optimizing care for breast cancer patients in various resource settings.

Elective egg freezing and its underlying socio-demography: a binational analysis with global implications.

BACKGROUND: What are the underlying socio-demographic factors that lead healthy women to preserve their fertility through elective egg freezing (EEF)? Many recent reviews suggest that women are intentionally postponing fertility through EEF to pursue careers and achieve reproductive autonomy. However, emerging empirical evidence suggests that women may be resorting to EEF for other reasons, primarily the lack of a partner with whom to pursue childbearing. The aim of this study is thus to understand what socio-demographic factors may underlie women's use of EEF. METHODS: A binational qualitative study was conducted from June 2014 to August 2016 to assess the socio-demographic characteristics and life circumstances of 150 healthy women who had undertaken at least one cycle of elective egg freezing (EEF) in the United States and Israel, two countries where EEF has been offered in IVF clinics over the past 7-8 years. One hundred fourteen American women who completed EEF were recruited from 4 IVF clinics in the US (2 academic, 2 private) and 36 women from 3 IVF clinics in Israel (1 academic, 2 private). In-depth, audio-recorded interviews lasting from 0.5 to 2 h were undertaken and later transcribed verbatim for qualitative data analysis. RESULTS: Women in both countries were educated professionals (100%), and 85% undertook EEF because they lacked a partner. This "lack of a partner" problem was reflected in women's own assessments of why they were single in their late 30s, despite their desires for marriage and childbearing. Women themselves assessed partnership problems from four perspectives: 1) women's higher expectations; 2) men's lower commitments; 3) skewed gender demography; and 4) self-blame. DISCUSSION: The "lack of a partner" problem reflects growing, but little discussed international socio-demographic disparities in educational achievement. University-educated women now significantly outnumber university-educated men in the US, Israel, and nearly 75 other societies around the globe, according to World Bank data. Thus, educated women increasingly face a deficit of educated men with whom to pursue childbearing. CONCLUSION: Among healthy women, EEF is a technological concession to gender-based socio-demographic disparities, which leave many highly educated women without partners during their prime childbearing years. This information is important for reproductive specialists who counsel single EEF patients, and for future research on EEF in diverse national settings.

Global alteration in gene expression profiles of deciduas from women with idiopathic recurrent pregnancy loss.

Recurrent pregnancy loss (RPL) occurs in ∼5% of women. However, the etiology is still poorly understood. Defects in decidualization of the endometrium during early pregnancy contribute to several pregnancy complications, such as pre-eclampsia and intrauterine growth restriction (IUGR), and are believed to be important in the pathogenesis of idiopathic RPL. We performed microarray analysis to identify gene expression alterations in the deciduas of idiopathic RPL patients. Control patients had one antecedent term delivery, but were undergoing dilation and curettage for current aneuploid miscarriage. Gene expression differences were evaluated using both pathway and gene ontology (GO) analysis. Selected genes were validated using quantitative reverse transcription-polymerase chain reaction (qRT-PCR). A total of 155 genes were found to be significantly dysregulated in the deciduas of RPL patients (>2-fold change, P < 0.05), with 22 genes up-regulated and 133 genes down-regulated. GO analysis linked a large percentage of genes to discrete biological functions, including immune response (23%), cell signaling (18%) and cell invasion (17.1%), and pathway analysis revealed consistent changes in both the interleukin 1 (IL-1) and IL-8 pathways. All genes in the IL-8 pathway were up-regulated while genes in the IL-1 pathway were down-regulated. Although both pathways can promote inflammation, IL-1 pathway activity is important for normal implantation. Additionally, genes known to be critical for degradation of the extracellular matrix, including matrix metalloproteinase 26 and serine peptidase inhibitor Kazal-type 1, were also highly up-regulated. In this first microarray approach to decidual gene expression in RPL patients, our data suggest that dysregulation of genes associated with cell invasion and immunity may contribute significantly to idiopathic recurrent miscarriage.

Normal pregnancy resulting from a non-pronuclear oocyte at the time of examination for fertilization.

PURPOSE: To report the case of a patient undergoing in vitro fertilization (IVF) in which a non-pronuclear (0PN) oocyte resulted in a normal pregnancy. METHODS: A 36-year-old woman underwent an IVF-embryo transfer treatment cycle. RESULTS: Four oocytes were retrieved for insemination by IVF. Examination for fertilization revealed two polypronuclearpolygynic and two non-pronuclear oocytes. The non-pronuclear oocytes were observed further for development. One embryo developed from the non-pronuclear cohort and was transferred at the 8-cell stage on day 3. Subsequently, a pregnancy developed, and resulted in the delivery of a healthy term infant. CONCLUSIONS: Non-pronuclear oocytes may represent a source of developmentally competent embryos, and further observation of this cohort should be considered, particularly in situations involving a low yield of oocytes at retrieval.

Double-blind, placebo-controlled study of Fertilityblend: a nutritional supplement for improving fertility in women.

PURPOSE: To determine the impact of nutritional supplementation on female fertility. METHODS: A double blind, placebo-controlled study of the effects of FertilityBlend for Women, a proprietary nutritional supplement containing chasteberry, green tea, L-arginine, vitamins (including folate) and minerals, on progesterone level, basal body temperature, menstrual cycle length, pregnancy rate and side-effects. RESULTS: Ninety-three (93) women, aged 24-42 years, who had tried unsuccessfully to conceive for six to 36 months, completed the study. After three months, the FertilityBlend (FB) group (N = 53) demonstrated a trend toward increased mean mid-luteal progesterone (P(ml)), but among women with basal pretreatment P(ml) < 9 ng/ml, the increase in progesterone was highly significant. The average number of days with luteal-phase basal temperatures over 98 degrees F increased significantly in the FB group. Both short and long cycles (< 27 days or > 32 days pretreatment) were normalized in the FB group. The placebo group (N = 40) did not show any significant changes in these parameters. After three months, 14 of the 53 women in the FB group were pregnant (26%) compared to four of the 40 women in the placebo group (10%; p = 0.01). Three additional women conceived after six months on FB (32%). No significant side-effects were noted. CONCLUSION: Nutritional supplements could provide an alternative or adjunct to conventional fertility therapies.

Comparison of GnRH antagonist cycles with and without oral contraceptive pretreatment in potential poor prognosis patients.

PURPOSE: To evaluate the effect of oral contraceptive pill (OCP) pretreatment in patients undergoing IVF cycles with an antagonist. METHODS: In this retrospective study, 194 cycles of women with diminished ovarian reserve undergoing IVF with a protocol using GnRH antagonists were evaluated. Oral contraceptive pretreatment was used in 146 cycles. RESULTS: Pregnancy rates were the same in both groups. Patients using OCPs required more gonadotropins (5,890 IU) compared to patients not undergoing OCP pretreatment (4,410 IU). CONCLUSIONS: Pregnancy outcomes were the same whether or not OCP pretreatment was implemented in poor responders using an antagonist protocol. While OCP pretreatment may help with scheduling flexibility, the higher dose of gonadotropins needed for ovarian stimulation should be considered.

Interleukin-1 type I receptor messenger ribonucleic acid expression in human endometrium throughout the menstrual cycle.

OBJECTIVE: To investigate the messenger ribonucleic acid (mRNA) expression of interleukin-1 (IL-1) type I receptor in the endometrial tissue of normal patients during the menstrual cycle. DESIGN: Prospective longitudinal study. SETTING: Department of Obstetrics and Gynecology, Stanford University Medical Center, Stanford, California. PATIENTS: Twenty fertile women between 19 and 41 years of age underwent hysterectomy for benign reasons (n = 9) and laparoscopy for tubal ligation (n = 11). In all cases, endometriosis was not visualized. INTERVENTIONS: Endometrial biopsy using the Novak curette was obtained at the time of surgery. MAIN OUTCOME MEASURE: Total RNA extracted from unfractioned endometrial tissue was analyzed on Northern blots by using specific complementary deoxyribonucleic acid probes. RESULTS: We found IL-1 type I receptor mRNA expression in endometrial tissue throughout the entire menstrual cycle. However, IL-1 type I receptor mRNA levels were significantly higher during both early and late luteal phases than follicular and midluteal phases. CONCLUSIONS: Our results demonstrate the presence of the IL-1 system in the human endometrium and that the receptor is regulated throughout the menstrual cycle with a 4.1-fold increased expression of the IL-1 receptor gene in the early luteal phase compared with preovulatory endometrium.

Comparison of propofol with methohexital for outpatient anesthesia.

Propofol is an intravenous anesthetic currently available for clinical investigative use. The intraoperative and postoperative effects of propofol were compared to methohexital when used as an adjuvant to nitrous oxide for outpatient anesthesia. Sixty healthy young women were randomly assigned to receive either methohexital, 1.5 mg/kg intravenously (IV), or propofol, 2.5 mg/kg IV, for induction of anesthesia. Both drugs produced transient cardiovascular and respiratory depression after induction. Maintenance of anesthesia consisted of either methohexital, 6 +/- 2 mg/min, or propofol, 7 +/- 2 mg/min (mean +/- SD) by continuous infusion in combination with nitrous oxide, 70% in oxygen. Use of a propofol infusion was associated with lower blood pressures and heart rates during maintenance. Propofol was associated with fewer side effects (e.g., hiccoughing, nausea, and vomiting) intra- and postoperatively. Recovery times for awakening, orientation, and ambulation were consistently shorter with propofol. We conclude that propofol is a useful alternative to methohexital for induction and maintenance of outpatient anesthesia.

Immunocytochemical localization of transforming growth factor-alpha and epidermal growth factor receptor in human fallopian tubes and cumulus cells.

PROBLEM: Transforming growth factor-alpha (TGF-alpha) has been shown to be a potent stimulant of oocyte maturation and embryonic development. The role of maternal growth factors and their mechanism of action in early mammalian development is not well understood. METHOD: In this study, the presence of TGF-alpha and epidermal growth factor receptor (EGF-R) in human cumulus cells and fallopian tubes was investigated by immunocytochemical techniques. RESULTS: The fallopian tube showed intense staining for TGF-alpha in the apical region of the epithelial cells, and the cumulus cells showed intense staining for EGF-R on cell membranes. CONCLUSION: The presence of TGF-alpha in the fallopian tube epithelium and its receptor on cumulus cells suggest a paracrine mechanism between maternal growth factors and the developing embryo.

First report of a vaginal foreign body perforating into the retroperitoneum.

Pelvic examination of a 19-year-old woman with recurrent pain after multiple laparotomies revealed a 4.0 cm paracervical fibroepithelial polyp and tender fullness in the left pelvis. Abdominal exploration had normal findings, but exploration of the retroperitoneum revealed an encysted bottle cap that had eroded through the vaginal wall years before.

Gonadotropins and the timing of progesterone-induced meiotic maturation of Xenopus laevis oocytes.

Isolated oocytes from 30 unstimulated Xenopus laevis females required from 2.50 +/- 0.13 to 14.59 +/- 0.77 hr after progesterone exposure for the first 50% of each group to complete meiotic maturation. Injecting 8 females with an amount of hCG not causing ovulation (25 micrograms, 96 IU) lowered oocyte maturation times by 45-83%. An enzyme-linked immunosorbent assay (ELISA) of the blood of 18 unstimulated animals found a constituent which bound to anti-hCG in amounts (equivalent to 0-1.03 micrograms/ml hCG) that had a direct relationship to the rates of GVBD in oocytes. Preincubation of manually isolated follicles in 0.25-1.25 micrograms/ml hCG shortens oocyte maturation times by 18-50% in a direct, nonlinear fashion and this priming effect is reversed when hCG is withdrawn. The action of gonadotropins in facilitating germinal vesicle breakdown (GVBD) mimics the previously reported priming effect produced by preincubation of oocytes in subthreshold levels of progesterone. Evidence suggests that individual variation in the time course of progesterone-induced meiotic maturation of amphibian oocytes is the result of priming differences caused by the action on follicle cells of fluctuating blood levels of an LH-like hormone.

Exposure of human spermatozoa to the cumulus oophorus results in increased relative force as measured by a 760 nm laser optical trap.

Spermatozoa change their movement characteristics in response to different environmental conditions. To investigate the relative force of spermatozoa exhibiting different motility patterns, a laser optical trap was used. A laser beam at 760 nm was directed through a microscope objective and focused above the spermatozoa to create a three-dimensional optical trap. Spermatozoa were trapped at 300 mW, and laser power was reduced until spermatozoa could escape. The force generated by the flagellar movement was proportional to the laser power at which the spermatozoa escaped from the trap. Three motility patterns were studied: linear, hyperactivated, and cumulus-related. Mean escape power for spermatozoa displaying linear motility was 59.5 +/- 43 mW, for hyperactivated motility 122.3 +/- 67 mW (P < 0.0001) and for cumulus-related motility 200.6 +/- 44.2 mW (P < 0.0001). In this study, we showed that human spermatozoa generated more relative force upon exposure to the cumulus mass. The combination of small-amplitude lateral head displacement and higher relative force may produce a 'drilling' effect which is synergistic with the enzymatic digestion of the cumulus matrix during the fertilization process.

Zona opening with 308 nm XeCl excimer laser improves fertilization by spermatozoa from long-term vasectomized mice.

Spermatozoa from long-term vasectomized mice have greatly reduced fertilizing ability in vivo and in vitro, which makes this a useful animal model for male factor infertility. The purpose of this study was to evaluate the 308 nm XeCl excimer laser for opening the zona pellucida to enhance the fertilization rate with spermatozoa from vasectomized males. Inseminating zona-intact (control) oocytes with 5 x 10(6) spermatozoa/ml resulted in only 6% fertilization and 33.3% development to the blastocyst stage; zona-opened oocytes showed significant improvement with 31.5% fertilization, 90% cleavage to the 2-cell stage, and 72.2% blastocyst formation. Out of the 130 oocytes in the experimental group, zona ablation was performed successfully on 127 and only three were damaged. These results suggest that laser micromanipulation for assisted fertilization potentially offers a simplified and precise method for mechanical zona cutting.

Administration of recombinant human FSH (solution in cartridge) with a pen device in women undergoing ovarian stimulation.

This study evaluated the first multiple-use pen device for the self-administration of recombinant FSH. The pen device is used for the subcutaneous injection of a pre-mixed ready-to-use solution of follitropin beta from a multiple-dose cartridge, and has flexible dosing capabilities. In the ease-of-use questionnaire, 90% of subjects rated the overall experience of self-injecting follitropin beta using the pen device as 'very good' (on day 6). The comprehension questionnaire revealed that prior to the first injection and during the second injection, the follitropin beta cartridge was properly loaded into the pen device by 96.7 and 100% of the subjects respectively. The questionnaire also showed that the correct dose was selected and self-administered by 98.3 and 100% of the subjects respectively. Biochemical and ongoing pregnancy rates per attempt were 56.7 and 45.0% respectively. The pen device is safe, effective, and easy to use for self-administering recombinant FSH during ovarian stimulation.