Creating an Artificial 3-Dimensional Ovarian Follicle Culture System Using a Microfluidic System.

We hypothesized that the creation of a 3-dimensional ovarian follicle, with embedded granulosa and theca cells, would better mimic the environment necessary to support early oocytes, both structurally and hormonally. Using a microfluidic system with controlled flow rates, 3-dimensional two-layer (core and shell) capsules were created. The core consists of murine granulosa cells in 0.8 mg/mL collagen + 0.05% alginate, while the shell is composed of murine theca cells suspended in 2% alginate. Somatic cell viability tests and hormonal assessments (estradiol, progesterone, and androstenedione) were performed on days 1, 6, 13, 20, and 27. Confocal microscopy confirmed appropriate compartmentalization of fluorescently-labeled murine granulosa cells to the inner capsule and theca cells to the outer shell. Greater than 78% of cells present in capsules were alive up to 27 days after collection. Artificially constructed ovarian follicles exhibited intact endocrine function as evidenced by the production of estradiol, progesterone, and androstenedione. Oocytes from primary and early secondary follicles were successfully encapsulated, which maintained size and cellular compartmentalization. This novel microfluidic system successfully encapsulated oocytes from primary and secondary follicles, recapitulating the two-compartment system necessary for the development of the mammalian oocyte. Importantly, this microfluidic system can be easily adapted for sterile, high throughput applications.

Follicle flushing does not improve live birth and increases procedure time: a systematic review and meta-analysis of randomized controlled trials.

OBJECTIVE: To determine whether follicle flushing during oocyte retrieval improves live birth or secondary outcomes in assisted reproductive technology (ART). DESIGN: Systematic review and meta-analysis. SETTING: Not applicable. PATIENT(S): Women undergoing ART using autologous gametes. INTERVENTION(S): A systematic search of PubMed, EMBASE, Cochrane Database, and Web of Science for randomized controlled trials comparing follicle flushing to direct aspiration during oocyte retrieval published in English between 1989 to 2020. MAIN OUTCOME MEASURE(S): Live birth as primary outcome, and clinical and ongoing pregnancy, total and mature metaphase II (MII) oocytes retrieved, and operating time as secondary outcomes. RESULT(S): Eleven studies were included totaling 1,178 cases. No difference in live birth was demonstrated between follicle flushing and direct aspiration. Clinical pregnancy and ongoing pregnancy were not improved with flushing. Total oocyte and MII yield were lower with flushing compared with direct aspiration. Procedure time was increased with flushing by 2 minutes in poor responders and 9 minutes in normal responders. Other sensitivity analyses did not demonstrate any changes, except the difference in MII yield was no longer statistically significant. CONCLUSION(S): Follicle flushing during oocyte retrieval increases procedure time and does not improve live birth or secondary ART outcomes. Randomized data do not support the use of follicle flushing as an intervention in ART.

Polycystic Ovarian Syndrome: Impact on Adult and Fetal Health.

Women with the polycystic ovarian syndrome (PCOS) may have an increased risk for complications in pregnancy including miscarriage, gestational diabetes mellitus, hypertensive disorders of pregnancy, higher rates of cesarean delivery, and abnormalities in fetal growth. In addition, PCOS has been associated with the development of type II diabetes mellitus, hypertension, cardiovascular disease, obstructive sleep apnea, endometrial cancer, depression and anxiety, and nonalcoholic fatty liver disease. In understanding that PCOS is a disease impacting more than just a woman's fertility, prevention and early identification of risk factors for affiliated conditions is essential.

Mature Follicle Count and Multiple Gestation Risk Based on Patient Age in Intrauterine Insemination Cycles With Ovarian Stimulation.

OBJECTIVE: To estimate the risk of a multiple gestation pregnancy in ovarian stimulation intrauterine insemination (IUI) cycles when stratified by patient age and mature follicle number. METHODS: We conducted a retrospective cohort study at a single private practice fertility center of IUI cycles performed from 2004 to 2017. Intervention(s) were ovarian stimulation and IUI if postwash total motile sperm count was more than 8 million. Mature follicles were defined as 14 mm or more as measured on the day of ovulation trigger. Main outcomes and measures were rates of clinical pregnancy and multiple gestation. RESULTS: We identified 24,649 women who underwent a total of 50,473 IUI cycles. Increasing the number of mature follicles from one to five at the time of IUI in women younger than age 38 years increased the clinical pregnancy rate from 14.6% to 21.9% (adjusted odds ratio [aOR] 1.6, 95% CI 1.4-1.9), almost entirely from a marked increase in multiple gestations per cycle from 0.6% to 6.5% (aOR 9.9, 95% CI 6.9-14.2). There was little increase in singleton pregnancies per IUI (14.1-16.4%) regardless of mature follicle number. The per-pregnancy twin and higher-order multiple gestation risk significantly increased (3.9-23.3%, P<.01 and 0.2-10.6%, P<.01, respectively) when comparing one with five mature follicles present at the time of IUI (P<.01). In women younger than age 38 years with more than three follicles present, more than one quarter of all pregnancies were multiples. Similar findings occurred in women aged 38-40 years. In women older than age 40 years, up to four follicles tripled the odds of pregnancy (aOR 3.1, 95% CI 2.1-4.5) while maintaining a less than 12% risk of multiple gestation per pregnancy and a 1.0% absolute risk of multiples. CONCLUSION: Caution should be used in proceeding with IUI after ovarian stimulation when there are more than two mature follicles in women younger than age 40 years owing to the substantially increased risk of multiple gestation without an improved chance of singleton clinical pregnancy.

Evaluation of the cost-effectiveness of ovulation suppression with progestins compared with GnRH analogs in assisted reproduction cycles.

RESEARCH QUESTION: Is ovulation suppression with progestins, requiring a freeze-all approach and subsequent frozen embryo transfer resulting from progestenic endometrial changes, cost-effective compared with gonadotropin releasing hormone analogues (GnRH) during assisted reproduction cycles. DESIGN: Cost-effectiveness analysis derived from a PubMed literature search of average US costs of GnRH agonist and antagonist IVF cycles. RESULTS: In all fresh IVF cycle models, progestin cycles were more expensive owing to the additional costs of increased gonadotropin use, embryo freezing and subsequent frozen embryo transfer (FET). The average cost per live birth with progestins ($32,466-$56,194) was higher than fresh IVF cycles with short (flare) GnRH agonist ($4,447-$12,797 higher) and GnRH antagonist ($1,542-$9,893 higher). When analyzing an initial embryo transfer plus additional FET in patients not initially pregnant, progestin cycles were still more expensive per live birth compared with conventional protocols. When planned freeze only cycles were analyzed, progestins became more cost-effective per live birth compared with antagonist cycles ($2,079 lower) but remained more expensive than short agonist cycles ($823 more expensive). CONCLUSIONS: Ovulation inhibition in IVF using progestins requires a freeze-only approach of embryos, and thus progestin use was not cost-effective compared with fresh embryo transfer cycles. Progestins, however, may be cost-effective compared with GnRH antagonist in planned freeze only cycles such as in preimplantation genetic testing or fertility preservation.

Adverse effect of prematurely elevated progesterone in in vitro fertilization cycles: a literature review.

Premature progesterone (P) elevation was commonly seen in IVF prior to the utilization of GnRH analogues for suppression of endogenous gonadotropin release. The cause and effect of premature P elevation has finally been better elucidated in the past decade. Although still occurring in 5-38% of all IVF cycles, the adverse effects of premature P elevation on pregnancy outcomes are now well known.

Progesterone luteal support after ovulation induction and intrauterine insemination: an updated systematic review and meta-analysis.

OBJECTIVE: To evaluate the effect of progesterone (P) for luteal phase support after ovulation induction (OI) and intrauterine insemination (IUI). DESIGN: An updated systematic review and meta-analysis. SETTING: Not applicable. PATIENT(S): Patients undergoing OI-IUI for infertility. INTERVENTION(S): Exogenous P luteal support after OI-IUI. MAIN OUTCOME MEASURE(S): Live birth. RESULT(S): Eleven trials were identified that met inclusion criteria and constituted 2,842 patients undergoing 4,065 cycles, more than doubling the sample size from the previous meta-analysis. In patients receiving gonadotropins for OI, clinical pregnancy (relative risk [RR] 1.56, 95% confidence interval [CI] 1.21-2.02) and live birth (RR 1.77, 95% CI 1.30-2.42) were more likely in P supplemented patients. These findings persisted in analysis of live birth per IUI cycle (RR 1.59, 95% CI 1.24-2.04). There were no data on live birth in clomiphene citrate or clomiphene plus gonadotropin cycles. There was no benefit on clinical pregnancy with P support for patients who underwent OI with clomiphene (RR 0.85, 95% CI 0.52-1.41) or clomiphene plus gonadotropins (RR 1.26, 95% CI 0.90-1.76). CONCLUSION(S): Progesterone luteal phase support is beneficial to patients undergoing ovulation induction with gonadotropins in IUI cycles. The number needed to treat is 11 patients to have one additional live birth. Progesterone support did not benefit patients undergoing ovulation induction with clomiphene citrate or clomiphene plus gonadotropins.