The prospect of artificial intelligence to personalize assisted reproductive technology.

Infertility affects 1-in-6 couples, with repeated intensive cycles of assisted reproductive technology (ART) required by many to achieve a desired live birth. In ART, typically, clinicians and laboratory staff consider patient characteristics, previous treatment responses, and ongoing monitoring to determine treatment decisions. However, the reproducibility, weighting, and interpretation of these characteristics are contentious, and highly operator-dependent, resulting in considerable reliance on clinical experience. Artificial intelligence (AI) is ideally suited to handle, process, and analyze large, dynamic, temporal datasets with multiple intermediary outcomes that are generated during an ART cycle. Here, we review how AI has demonstrated potential for optimization and personalization of key steps in a reproducible manner, including: drug selection and dosing, cycle monitoring, induction of oocyte maturation, and selection of the most competent gametes and embryos, to improve the overall efficacy and safety of ART.

Endocrine Requirements for Oocyte Maturation Following hCG, GnRH Agonist, and Kisspeptin During IVF Treatment.

Objective: The maturation of oocytes to acquire competence for fertilization is critical to the success of in vitro fertilization (IVF) treatment. It requires LH-like exposure, provided by either human chorionic gonadotropin (hCG), or gonadotropin releasing hormone agonist (GnRHa). More recently, the hypothalamic stimulator, kisspeptin, was used to mature oocytes. Herein, we examine the relationship between the endocrine changes following these agents and oocyte maturation. Design: Retrospective cohort study. Methods: Prospectively collected hormonal data from 499 research IVF cycles triggered with either hCG, GnRHa, or kisspeptin were evaluated. Results: HCG-levels (121 iU/L) peaked at 24 h following hCG, whereas LH-levels peaked at ~4 h following GnRHa (140 iU/L), or kisspeptin (41 iU/L). HCG-levels were negatively associated with body-weight, whereas LH rises following GnRHa and kisspeptin were positively predicted by pre-trigger LH values. The odds of achieving the median mature oocyte yield for each trigger were increased by hCG/LH level. Progesterone rise during oocyte maturation occurred precipitously following each trigger and strongly predicted the number of mature oocytes retrieved. Progesterone rise was positively associated with the hCG-level following hCG trigger, but negatively with LH rise following all three triggers. The rise in progesterone per mature oocyte at 12 h was greater following GnRHa than following hCG or kisspeptin triggers. Conclusion: The endocrine response during oocyte maturation significantly differed by each trigger. Counter-intuitively, progesterone rise during oocyte maturation was negatively associated with LH rise, even when accounting for the number of mature oocytes retrieved. These data expand our understanding of the endocrine changes during oocyte maturation and inform the design of future precision-triggering protocols.

Anti-Müllerian hormone (AMH) in the Diagnosis of Menstrual Disturbance Due to Polycystic Ovarian Syndrome.

Introduction: Polycystic ovarian syndrome (PCOS) is a leading cause of female subfertility worldwide, however due to the heterogeneity of the disorder, the criteria for diagnosis remains subject to conjecture. In the present study, we evaluate the utility of serum Anti-Müllerian hormone (AMH) in the diagnosis of menstrual disturbance due to PCOS. Method: Menstrual cycle length, serum AMH, gonadotropin and sex-hormone levels, total antral follicle count (AFC), body mass index (BMI) and ovarian morphology on ultrasound were analyzed in a cohort of 187 non-obese women, aged 18-35 years, screened for participation in a clinical trial of fertility treatment between 2013 and 2016 at a tertiary reproductive endocrine center. Results: Serum AMH was higher in women with menstrual disturbance when compared to those with regular cycles (65.6 vs. 34.8 pmol/L; P < 0.0001). The odds of menstrual disturbance was increased 28.5-fold (95% CI 3.6-227.3) in women with serum AMH >60 pmol/L, in comparison to those with an AMH < 15 pmol/L. AMH better discriminated women with menstrual disturbance (area under ROC 0.77) from those with regular menstrual cycles than AFC (area under ROC 0.67), however the combination of the two markers increased discrimination than either measure alone (0.83; 95% CI 0.77-0.89). Serum AMH was higher in women with all three cardinal features of PCOS (menstrual disturbance, hyperandrogenism, polycystic ovarian morphology) when compared to women with none of these features (65.6 vs. 14.6 pmol/L; P < 0.0001). The odds of menstrual disturbance were increased by 10.7-fold (95% CI 2.4-47.1) in women with bilateral polycystic morphology ovaries than those with normal ovarian morphology. BMI was a stronger predictor of free androgen index (FAI) than either AMH or AFC. Conclusion: Serum AMH could serve as a useful biomarker to indicate the risk of menstrual disturbance due to PCOS. Women with higher AMH levels had increased rates of menstrual disturbance and an increased number of features of PCOS.

FSH Requirements for Follicle Growth During Controlled Ovarian Stimulation.

Introduction: Ovarian follicle growth is a key step in the success of assisted reproductive treatment, but limited data exists to directly relate follicle growth to recombinant FSH (rFSH) dose. In this study, we aim to evaluate FSH requirements for follicular growth during controlled ovarian stimulation. Method: Single center retrospective cohort study of 1,034 IVF cycles conducted between January 2012-January 2016 at Hammersmith Hospital IVF unit, London, UK. Median follicle size after 5 days of stimulation with rFSH and the proportion of antral follicles recruited were analyzed in women treated with rFSH alone to induce follicular growth during IVF treatment. Results: Starting rFSH dose adjusted for body weight (iU/kg) predicted serum FSH level after 5 days of rFSH (r 2 = 0.352, p < 0.0001), median follicle size after 5 days of rFSH, and the proportion of antral follicles recruited by the end of stimulation. Day 5 median follicle size predicted median follicle size on subsequent ultrasound scans (r 2 = 0.58-0.62; p < 0.0001), and hence time to oocyte maturation trigger (r 2 = 0.22, P < 0.0001). Insufficient rFSH starting dose that required >5% dose-increase was associated with increased variability in follicle size on the day of oocyte maturation trigger, and negatively impacted the number of mature oocytes retrieved. Conclusion: Weight-adjusted rFSH dose correlates with follicular growth during ovarian stimulation. Early recruitment of follicles using a sufficient dose of rFSH from the start of stimulation was associated with reduced variability in follicle size at time of oocyte maturation trigger and an increased number of mature oocytes retrieved.

Follicle Size on Day of Trigger Most Likely to Yield a Mature Oocyte.

OBJECTIVE: To identify follicle sizes on the day of trigger most likely to yield a mature oocyte following hCG, GnRH agonist (GnRHa), or kisspeptin during IVF treatment. DESIGN: Retrospective analysis to determine the size of follicles on day of trigger contributing most to the number of mature oocytes retrieved using generalized linear regression and random forest models applied to data from IVF cycles (2014-2017) in which either hCG, GnRHa, or kisspeptin trigger was used. SETTING: HCG and GnRHa data were collected at My Duc Hospital, Ho Chi Minh City, Vietnam, and kisspeptin data were collected at Hammersmith Hospital, London, UK. PATIENTS: Four hundred and forty nine women aged 18-38 years with antral follicle counts 4-87 were triggered with hCG (n = 161), GnRHa (n = 165), or kisspeptin (n = 173). MAIN OUTCOME MEASURE: Follicle sizes on the day of trigger most likely to yield a mature oocyte. RESULTS: Follicles 12-19 mm on the day of trigger contributed the most to the number of oocytes and mature oocytes retrieved. Comparing the tertile of patients with the highest proportion of follicles on the day of trigger 12-19 mm, with the tertile of patients with the lowest proportion within this size range, revealed increases of 4.7 mature oocytes for hCG (P < 0.0001) and 4.9 mature oocytes for GnRHa triggering (P < 0.01). Using simulated follicle size profiles of patients with 20 follicles on the day of trigger, our model predicts that the number of oocytes retrieved would increase from a mean 9.8 (95% prediction limit 9.3-10.3) to 14.8 (95% prediction limit 13.3-16.3) oocytes due to the difference in follicle size profile alone. CONCLUSION: Follicles 12-19 mm on the morning of trigger administration were most likely to yield a mature oocyte following hCG, GnRHa, or kisspeptin.

A second dose of kisspeptin-54 improves oocyte maturation in women at high risk of ovarian hyperstimulation syndrome: a Phase 2 randomized controlled trial.

STUDY QUESTION: Can increasing the duration of LH-exposure with a second dose of kisspeptin-54 improve oocyte maturation in women at high risk of ovarian hyperstimulation syndrome (OHSS)? SUMMARY ANSWER: A second dose of kisspeptin-54 at 10 h following the first improves oocyte yield in women at high risk of OHSS. WHAT IS KNOWN ALREADY: Kisspeptin acts at the hypothalamus to stimulate the release of an endogenous pool of GnRH from the hypothalamus. We have previously reported that a single dose of kisspeptin-54 results in an LH-surge of ~12-14 h duration, which safely triggers oocyte maturation in women at high risk of OHSS. STUDY DESIGN, SIZE, DURATION: Phase-2 randomized placebo-controlled trial of 62 women at high risk of OHSS recruited between August 2015 and May 2016. Following controlled ovarian stimulation, all patients (n = 62) received a subcutaneous injection of kisspeptin-54 (9.6 nmol/kg) 36 h prior to oocyte retrieval. Patients were randomized 1:1 to receive either a second dose of kisspeptin-54 (D; Double, n = 31), or saline (S; Single, n = 31) 10 h thereafter. Patients, embryologists, and IVF clinicians remained blinded to the dosing allocation. PARTICIPANTS/MATERIALS, SETTING, METHODS: Study participants: Sixty-two women aged 18-34 years at high risk of OHSS (antral follicle count ≥23 or anti-Mullerian hormone level ≥40 pmol/L). Setting: Single centre study carried out at Hammersmith Hospital IVF unit, London, UK. Primary outcome: Proportion of patients achieving an oocyte yield (percentage of mature oocytes retrieved from follicles ≥14 mm on morning of first kisspeptin-54 trigger administration) of at least 60%. Secondary outcomes: Reproductive hormone levels, implantation rate and OHSS occurrence. MAIN RESULTS AND THE ROLE OF CHANCE: A second dose of kisspeptin-54 at 10 h following the first induced further LH-secretion at 4 h after administration. A higher proportion of patients achieved an oocyte yield ≥60% following a second dose of kisspeptin-54 (Single: 14/31, 45%, Double: 21/31, 71%; absolute difference +26%, CI 2-50%, P = 0.042). Patients receiving two doses of kisspeptin-54 had a variable LH-response following the second kisspeptin dose, which appeared to be dependent on the LH-response following the first kisspeptin injection. Patients who had a lower LH-rise following the first dose of kisspeptin had a more substantial 'rescue' LH-response following the second dose of kisspeptin. The variable LH-response following the second dose of kisspeptin resulted in a greater proportion of patients achieving an oocyte yield ≥60%, but without also increasing the frequency of ovarian over-response and moderate OHSS (Single: 1/31, 3.2%, Double: 0/31, 0%). LIMITATIONS, REASONS FOR CAUTION: Further studies are warranted to directly compare kisspeptin-54 to more established triggers of oocyte maturation. WIDER IMPLICATIONS OF THE FINDINGS: Triggering final oocyte maturation with kisspeptin is a novel therapeutic option to enable the use of fresh embryo transfer even in the woman at high risk of OHSS. STUDY FUNDING/COMPETING INTEREST(S): The study was designed, conducted, analysed and reported entirely by the authors. The Medical Research Council (MRC), Wellcome Trust & National Institute of Health Research (NIHR) provided research funding to carry out the studies. There are no competing interests to declare. TRIAL REGISTRATION NUMBER: Clinicaltrial.gov identifier NCT01667406. TRIAL REGISTRATION DATE: 8 August 2012. DATE OF FIRST PATIENT'S ENROLMENT: 10 August 2015.

A first-in-human, randomized, controlled, subject- and reviewer-blinded multicenter study of Actamax™ Adhesion Barrier.

PURPOSE: Post-surgical adhesions remain a significant concern following abdominopelvic surgery. This study was to assess safety, manageability and explore preliminary efficacy of applying a degradable hydrogel adhesion barrier to areas of surgical trauma following gynecologic laparoscopic abdominopelvic surgery. METHODS: This first-in-human, prospective, randomized, multicenter, subject- and reviewer-blinded clinical study was conducted in 78 premenopausal women (18-46 years) wishing to maintain fertility and undergoing gynecologic laparoscopic abdominopelvic surgery with planned clinically indicated second-look laparoscopy (SLL) at 4-12 weeks. The first two patients of each surgeon received hydrogel, up to 30 mL sprayed over all sites of surgical trauma, and were assessed for safety and application only (n = 12). Subsequent subjects (n = 66) were randomized 1:1 to receive either hydrogel (Treatment, n = 35) or not (Control, n = 31); 63 completed the SLL. RESULTS: No adverse event was assessed as serious, or possibly device related. None was severe or fatal. Adverse events were reported for 17 treated subjects (17/47, 36.2%) and 13 Controls (13/31, 41.9%). For 95.7% of treated subjects, surgeons found the device "easy" or "very easy" to use; in 54.5%, some residual material was evident at SLL. For 63 randomized subjects who completed the SLL, adjusted between-group difference in the change from baseline adhesion score demonstrated a 41.4% reduction for Treatment compared with Controls (p = 0.017), with a 49.5% reduction (p = 0.008) among myomectomy subjects (n = 34). CONCLUSION: Spray application of a degradable hydrogel adhesion barrier during gynecologic laparoscopic abdominopelvic surgery was performed easily and safely, without evidence of clinically significant adverse outcomes. Data suggest the hydrogel was effective in reducing postoperative adhesion development, particularly following myomectomy.

Efficacy of Kisspeptin-54 to Trigger Oocyte Maturation in Women at High Risk of Ovarian Hyperstimulation Syndrome (OHSS) During In Vitro Fertilization (IVF) Therapy.

CONTEXT: In vitro fertilization (IVF) treatment is an effective therapy for infertility, but can result in the potentially life-threatening complication, ovarian hyperstimulation syndrome (OHSS). OBJECTIVE: This study aimed to investigate whether kisspeptin-54 can be used to effectively and safely trigger oocyte maturation in women undergoing IVF treatment at high risk of developing OHSS. SETTING AND DESIGN: This was a phase 2, multi-dose, open-label, randomized clinical trial of 60 women at high risk of developing OHSS carried out during 2013-2014 at Hammersmith Hospital IVF unit, London, United Kingdom. INTERVENTION: Following a standard recombinant FSH/GnRH antagonist protocol, patients were randomly assigned to receive a single injection of kisspeptin-54 to trigger oocyte maturation using an adaptive design for dose allocation (3.2 nmol/kg, n = 5; 6.4 nmol/kg, n = 20; 9.6 nmol/kg, n = 15; 12.8 nmol/kg, n = 20). Oocytes were retrieved 36 h after kisspeptin-54 administration, assessed for maturation, and fertilized by intracytoplasmic sperm injection with subsequent transfer of one or two embryos. Women were routinely screened for the development of OHSS. MAIN OUTCOME MEASURE: Oocyte maturation was measured by oocyte yield (percentage of mature oocytes retrieved from follicles ≥ 14 mm on ultrasound). Secondary outcomes include rates of OHSS and pregnancy. RESULTS: Oocyte maturation occurred in 95% of women. Highest oocyte yield (121%) was observed following 12.8 nmol/kg kisspeptin-54, which was +69% (confidence interval, -16-153%) greater than following 3.2 nmol/kg. At all doses of kisspeptin-54, biochemical pregnancy, clinical pregnancy, and live birth rates per transfer (n = 51) were 63, 53, and 45%, respectively. Highest pregnancy rates were observed following 9.6 nmol/kg kisspeptin-54 (85, 77, and 62%, respectively). No woman developed moderate, severe, or critical OHSS. CONCLUSION: Kisspeptin-54 is a promising approach to effectively and safely trigger oocyte maturation in women undergoing IVF treatment at high risk of developing OHSS.

Kisspeptin-54 triggers egg maturation in women undergoing in vitro fertilization.

BACKGROUND: Patients with mutations that inactivate kisspeptin signaling are infertile. Kisspeptin-54, the major circulating isoform of kisspeptin in humans, potently stimulates reproductive hormone secretion in humans. Animal studies suggest that kisspeptin is involved in generation of the luteinizing hormone surge, which is required for ovulation; therefore, we hypothesized that kisspeptin-54 could be used to trigger egg maturation in women undergoing in vitro fertilization therapy. METHODS: Following superovulation with recombinant follicle-stimulating hormone and administration of gonadotropin-releasing hormone antagonist to prevent premature ovulation, 53 women were administered a single subcutaneous injection of kisspeptin-54 (1.6 nmol/kg, n = 2; 3.2 nmol/kg, n = 3; 6.4 nmol/kg, n = 24; 12.8 nmol/kg, n = 24) to induce a luteinizing hormone surge and egg maturation. Eggs were retrieved transvaginally 36 hours after kisspeptin injection, assessed for maturation (primary outcome), and fertilized by intracytoplasmic sperm injection with subsequent transfer of one or two embryos. RESULTS: Egg maturation was observed in response to each tested dose of kisspeptin-54, and the mean number of mature eggs per patient generally increased in a dose-dependent manner. Fertilization of eggs and transfer of embryos to the uterus occurred in 92% (49/53) of kisspeptin-54-treated patients. Biochemical and clinical pregnancy rates were 40% (21/53) and 23% (12/53), respectively. CONCLUSION: This study demonstrates that a single injection of kisspeptin-54 can induce egg maturation in women with subfertility undergoing in vitro fertilization therapy. Subsequent fertilization of eggs matured following kisspeptin-54 administration and transfer of resulting embryos can lead to successful human pregnancy. TRIAL REGISTRATION: ClinicalTrials.gov NCT01667406.

Role of Insulin-like growth factors in initiation of follicle growth in normal and polycystic human ovaries.

CONTEXT: Polycystic ovary syndrome (PCOS), the commonest cause of anovulatory infertility, is characterized by disordered follicle development including increased activation and accelerated growth of preantral follicles. Data from experimental animals and preliminary results from studies of human ovarian tissue suggest that IGFs affect preantral follicle development. OBJECTIVE: Our objectives were to investigate the expression of the type-1 IGF receptor (IGFR-1) in the human ovary and to determine whether IGFs are involved in stimulating the transition of follicles from primordial to primary stage in normal and polycystic ovaries. DESIGN: We used archived ovarian tissue for protein expression studies and small cortical biopsies for follicle isolation and for tissue culture. SETTING: This was a laboratory-based study, using clinical tissue samples. PATIENTS: A total of 54 women, 33 with normal ovaries and 21 with polycystic ovaries, were classified by reference to menstrual cycle history and ultrasonography. MAIN OUTCOME MEASURES: We evaluated expression of IGFR-1 mRNA in isolated preantral follicles and of IGFR-1 protein in archived ovarian tissue samples from normal and polycystic ovaries and effects of exogenous IGF-1 on preantral follicle development and survival in cultured fragments of normal and polycystic ovaries. RESULTS: IGFR-1 mRNA and protein was expressed in preantral follicles at all stages of development and enhanced expression was noted in PCOS follicles during early preantral development. IGF-1 stimulated initiation of follicle growth in normal tissue but had little effect on preantral follicle growth in polycystic ovaries in which, characteristically, there was a higher proportion of follicles that had entered the growing phase even before culture. CONCLUSIONS: IGFs are plausible candidates in regulation of initiation of human follicle growth, and accelerated preantral follicle growth in PCOS may be due to increased activity of endogenous IGFs.

In vitro fertilisation with recombinant follicle stimulating hormone requires less IU usage compared with highly purified human menopausal gonadotrophin: results from a European retrospective observational chart review.

BACKGROUND: Previous studies have reported conflicting results for the comparative doses of recombinant follicle stimulating hormone (rFSH) and highly purified human menopausal gonadotrophin (hMG-HP) required per cycle of in vitro fertilisation (IVF); the aim of this study was to determine the average total usage of rFSH versus hMG-HP in a 'real-world' setting using routine clinical practice. METHODS: This retrospective chart review of databases from four European countries investigated gonadotrophin usage, oocyte and embryo yield, and pregnancy outcomes in IVF cycles (± intra-cytoplasmic sperm injection) using rFSH or hMG-HP alone. Included patients met the National Institute for Health and Clinical Excellence (NICE) guideline criteria for IVF and received either rFSH or hMG-HP. Statistical tests were conducted at 5% significance using Chi-square or t-tests. RESULTS: Of 30,630 IVF cycles included in this review, 74% used rFSH and 26% used hMG-HP. A significantly lower drug usage per cycle for rFSH than hMG-HP (2072.53 +/- 76.73 IU vs. 2540.14 +/- 883.08 IU, 22.6% higher for hMG-HP; p < 0.01) was demonstrated. The median starting dose was also significantly lower for rFSH than for hMG-HP (150 IU vs. 225 IU, 50% higher for hMG-HP, p < 0.01). The average oocyte yield per IVF cycle in patients treated with rFSH was significantly greater than with hMG-HP (10.80 +/- 6.02 vs. 9.77 +/- 5.53; p < 0.01), as was the average mature oocyte yield (8.58 +/- 5.27 vs. 7.72 +/- 4.59; p < 0.01). No significant differences were observed in pregnancy outcomes including spontaneous abortion between the two treatments. There was a significantly higher rate of OHSS (all grades) with rFSH (18.92% vs. 14.09%; p < 0.0001). The hospitalisation rate due to OHSS was low but significantly higher in the rFSH group (1.07% of cycles started vs. 0.67% of cycles started with rFSH and hMG-HP, respectively; p = 0.002). CONCLUSIONS: Based on these results, IVF treatment cycles with rFSH yield statistically more oocytes (and more mature oocytes), using significantly less IU per cycle, versus hMG-HP. The incidence of all OHSS and hospitalisations due to OHSS was significantly higher in the rFSH cycles compared to the hMG-HP cycles. However, the absolute incidence of hospitalisations due to OHSS was similar to that reported previously. These results suggest that the perceived required dosage with rFSH is currently over-estimated, and the higher unit cost of rFSH may be offset by a lower required dosage compared with hMG-HP.

Congenital uterine anomalies and their impact on fertility.

Congenital uterine anomalies are not uncommon. Many are asymptomatic and have been associated with normal and adverse reproductive outcomes. The interference of these anomalies with a patient's fertility is an interesting but still debatable issue, and the proper management of infertile women with many forms of these anomalies remains controversial. The current literature regarding the frequency and probable causes of infertility among women with congenital uterine anomalies is insufficient to allow any robust conclusions to be drawn. Diagnostic and selection bias, a lack of objective diagnostic criteria for the different anomaly types and heterogeneity of study designs have contributed to the conflicting results from different studies of the prevalence of these anomalies among the infertile and fertile populations. However, emerging evidence from recent literature suggests causal associations between these anomalies (particularly the septate uterus) and infertility, and demonstrates significant improvements in the fecundity of women with septate uteri and otherwise unexplained infertility after hysteroscopic metroplasty. This review provides a critical update of the state of knowledge regarding congenital uterine anomalies, our current understanding of their effect on fertility and discusses how they can be managed from the reproductive perspective.

Infertile women with isolated polycystic ovaries are deficient in endometrial expression of osteopontin but not alphavbeta3 integrin during the implantation window.

OBJECTIVE: To characterize possible endometrial defects in infertile women with isolated PCO morphology. DESIGN: Prospective study. SETTING: An academic hospital with an IVF unit. PATIENT(S): Women with primary unexplained infertility and isolated PCO, fertile women, and women with infertility secondary to male factor. INTERVENTION(S): Thirty-one women (fertile and with male factor infertility) had endometrial sampling across the menstrual cycle. Nine fertile women and 10 infertile women with isolated PCO had sampling on day LH +7, adjusted for histologic dating. MAIN OUTCOME MEASURE(S): Expression of alphavbeta3 and its ligand, osteopontin, were determined using real-time quantitative polymerase chain reaction and immunohistochemistry. In vitro regulation of osteopontin was assessed using the Ishikawa cell line. RESULT(S): Cyclic variations revealed a fall in integrin alphavbeta3 mRNA during the secretory phase with concomitant up-regulation of osteopontin mRNA. Immunohistochemistry on day LH +7 demonstrated a significant reduction in expression of osteopontin in the isolated PCO group with no difference in expression of alphavbeta3. In vitro studies confirmed up-regulation of osteopontin by estrogen with no apparent effect of androgen. CONCLUSION(S): These results demonstrate an apparent reduction of osteopontin expression, important in cell-cell adhesion, during the window of implantation in infertile women with isolated PCO morphology.

Prolonged survival in culture of preantral follicles from polycystic ovaries.

CONTEXT: In polycystic ovary syndrome (PCOS), an increased proportion of follicles leave the primordial (resting) pool and initiate growth. However, there is little evidence for a reduced reproductive life span (early menopause) in women with PCOS, suggesting that the dynamics of follicle growth, and of follicle loss by atresia, is altered in PCOS. OBJECTIVE: The aim of this study was to investigate the possibility that loss of preantral follicles by atresia is reduced in PCOS, leading to prolonged follicle survival. DESIGN: We compared follicle growth in normal and polycystic ovaries using cultures of small ovarian biopsies. SETTING: Tissue samples were obtained at routine laparoscopy from 12 patients with anovulatory PCOS and 16 controls and processed in an ovarian physiology laboratory. MAIN OUTCOME MEASURES: We performed morphometric analysis of follicle population in tissue fixed at time of biopsy (d 0) or after 5, 10, or 15 d in culture. Analyses included assessment of follicle and oocyte diameter, number and proportion of primordial and growing follicles, and number and proportion of atretic follicles. RESULTS: In tissue fixed on d 0, the proportion of healthy growing follicles was, as expected, greater in ovaries from PCOS patients than in normal ovaries (64 vs. 28%; P = 0.0005), but there were no differences between PCOS and normal tissue during culture. The rate of atresia throughout the period of culture in follicles was, however, significantly lower in PCOS tissue (P < 0.0001). After culture, 80% of follicles in normal ovarian tissue were atretic compared with 53% in PCOS biopsies. CONCLUSION: Follicles from polycystic ovaries demonstrate a decreased rate of atresia in culture, suggesting a mechanism for maintaining a larger follicle pool throughout reproductive life.

Maternal C-reactive protein levels in patients undergoing frozen embryo replacement cycles: a prospective study.

This prospective study shows that the early pregnancy inflammatory response following frozen embryo replacement (FER) cycles may be absent or suppressed, in contrast to that following IVF. To our knowledge, this is the first study to evaluate the maternal inflammatory response following FER cycles, but larger studies are still required to explore this novel finding, and investigate whether this may explain the lower ongoing pregnancy rates generally achieved following FER cycles.

Thrombocythemia and hemoperitoneum after transvaginal oocyte retrieval for in vitro fertilization.

OBJECTIVE: To present the first report of massive hemoperitoneum in a case of essential thrombocythemia after transvaginal oocyte retrieval for IVF and review the relevant literature related to the management of patients with this condition. DESIGN: Case report. SETTING: Assisted conception unit of a tertiary care university hospital in the United Kingdom. PATIENT(S): A 37-year-old woman with essential thrombocythemia who developed massive intra-abdominal bleeding after transvaginal oocyte retrieval for IVF. INTERVENTION(S): Emergency laparotomy and right salpingoophorectomy. RESULT(S): Resuscitation of the patient. MAIN OUTCOME MEASURE(S): Overall management of the patient is discussed. CONCLUSION(S): The management of patients with essential thrombocythemia at the childbearing period poses a difficult problem. Fertility may be reduced, and an adverse outcome of pregnancy due to thrombotic or bleeding complications is a matter of concern. A multidisciplinary approach with close and early cooperation with the hematologists before initiation of IVF therapy for patients with essential thrombocythemia is essential. Efforts should be made to reduce the platelet count and assess the platelet function before embarking on IVF, keeping in mind the double jeopardy from bleeding and thrombosis in these cases.

Optimizing gonadotrophin-releasing hormone antagonist protocols.

The introduction of the gonadotrophin-releasing hormone(GnRH) antagonists offers new potential for in vitro fertilization (IVF) clinics. Compared with GnRH agonists, the use of the GnRH antagonists significantly reduces the dose of gonadotrophin and duration of treatment required, and also reduces unwanted side-effects. Patients also tend to prefer treatment with GnRH antagonists compared with agonists. The GnRH antagonists are useful in both good and poor responders, and there is some flexibility in treatment protocols. A single dose of GnRH antagonist may be used in patients who do not want or require more aggressive stimulation. Promising data indicate advantages of GnRH antagonists in terms of reduced incidence of ovarian hyperstimulation syndrome and reduced impairment of luteal function. It is anticipated that, as a result of further development of treatment protocols, pregnancy rates with the GnRH antagonists will become at least equivalent to those achieved with GnRH agonist protocols.