Tim Child

In vitro maturation or in vitro fertilization for women with polycystic ovaries? A case–control study of 194 treatment cycles

OBJECTIVE To compare the outcome of unstimulated in vitro maturation (IVM) and routine IVF/intracytoplasmic sperm injection (ICSI) for women with polycystic ovaries (PCO). DESIGN Retrospective case-control study. SETTING Fertility unit. PATIENT(S) Ninety-seven patients undergoing IVM were compared with 97 patients undergoing IVF. All had PCO and matched for age, infertility diagnosis, and ovulatory status. INTERVENTION(S) In vitro maturation cycles were unstimulated and hCG was administered 35-40 hours before oocyte retrieval. Oocytes were matured in vitro for 24-48 hours before insemination by ICSI. Endometrial priming with E(2) and P was commenced from the day of egg retrieval and one to two embryos were transferred on days 2-5 of development. Standard long protocol IVF/ICSI was used in the control group. MAIN OUTCOME MEASURE(S) Live birth rate per cycle and ovarian hyperstimulation syndrome (OHSS) rate. RESULT(S) Overall, 65% of IVM eggs matured in vitro in the IVM group. Implantation rates were significantly higher in the IVF group (19.4% vs. 12.9%) as clinical pregnancy rates (50.5% vs. 19.6%) and live birth rates (44.3% vs. 16.5%) than in the IVM group. The OHSS rate was significantly higher in the IVF group (8.2% vs. 0%). CONCLUSION(S) In vitro maturation is a safer and simpler alternative to conventional IVF for women with PCO. It avoids difficulties of gonadotropin stimulation and the risk of OHSS but has a significantly lower live birth rate. Current research projects aim to close the success gap between IVM and IVF.

Clomifene citrate or low-dose FSH for the first-line treatment of infertile women with anovulation associated with polycystic ovary syndrome: a prospective randomized multinational study

BACKGROUND Clomifene citrate (CC) is accepted as the first-line method for ovulation induction (OI) in patients with polycystic ovary syndrome (PCOS) associated with infertility owing to anovulation. Low-dose FSH has been reserved for women failing to conceive with CC. In this RCT, we tested the hypothesis that pregnancy rate (PR) and live birth rates (LBR) are higher after OI with low-dose FSH than with CC as first-line treatment. METHODS Infertile women (<40 years old) with PCOS-related anovulation, without prior OI treatment, attending 10 centres in Europe/South America were randomized to OI with either CC (50-150 mg/day for 5 days) or FSH (starting dose 50 IU) for up to three treatment cycles. The primary outcome was clinical PR. RESULTS Patients (n = 302) were randomized to OI with FSH (n = 132 women; 288 cycles) or CC (n = 123; 310 cycles). Per protocol analysis revealed that reproductive outcome was superior after OI with FSH than with CC with respect to PR per first cycle [30 versus 14.6%, respectively, 95% confidence interval (CI) 5.3-25.8, P = 0.003], PR per woman, (58 versus 44% of women, 95% CI 1.5-25.8, P = 0.03), LBR per woman (52 versus 39%, 95% CI 0.4-24.6, P = 0.04), cumulative PR (52.1 versus 41.2%, P = 0.021) and cumulative LBR (47.4 versus 36.9%, P = 0.031), within three cycles of OI. CONCLUSIONS Pregnancies and live births are achieved more effectively and faster after OI with low-dose FSH than with CC. This result has to be balanced by convenience and cost in favour of CC. FSH may be an appropriate first-line treatment for some women with PCOS and anovulatory infertility, particularly older patients.

IVF outcome in women with PCOS, PCO and normal ovarian morphology

OBJECTIVE To examine the outcome of IVF in women who have normal ovaries, ovulatory PCO or PCOS. STUDY DESIGN Analysis of a prospectively collected database in an assisted conception unit in a university teaching hospital including 290 women <37 years of age undergoing their first IVF cycle. The main outcome measure was severe OHSS requiring hospitalization. RESULTS Severe OHSS rates were significantly higher in women with PCO (12.6%) and PCOS (15.4%) compared to those with normal ovaries (2.7%). Coasting was used significantly more often. Live birth rates per cycle started are similar among women with PCO (38%), PCOS (37%) and normal ovaries (40%). CONCLUSION Women with ovaries of polycystic morphology are at increased risk of developing severe OHSS and of requiring avoidance techniques such as coasting, regardless of ovulatory status. However, live birth rates per cycle are similar to women with normal ovaries.

ST2 and IL-33 in Pregnancy and Pre-Eclampsia

Normal pregnancy is associated with a mild systemic inflammatory response and an immune bias towards type 2 cytokine production, whereas pre-eclampsia is characterized by a more intense inflammatory response, associated with endothelial dysfunction and a type 1 cytokine dominance. Interleukin (IL)-33 is a newly described member of the IL-1 family, which binds its receptor ST2L to induce type 2 cytokines. A soluble variant of ST2 (sST2) acts as a decoy receptor to regulate the activity of IL-33. In this study circulating IL-33 and sST2 were measured in each trimester of normal pregnancy and in women with pre-eclampsia. While IL-33 did not change throughout normal pregnancy, or between non-pregnant, normal pregnant or pre-eclamptic women, sST2 was significantly altered. sST2 was increased in the third trimester of normal pregnancy (p<0.001) and was further increased in pre-eclampsia (p<0.001). This increase was seen prior to the onset of disease (p<0.01). Pre-eclampsia is a disease caused by placental derived factors, and we show that IL-33 and ST2 can be detected in lysates from both normal and pre-eclampsia placentas. ST2, but not IL-33, was identified on the syncytiotrophoblast layer, whereas IL-33 was expressed on perivascular tissue. In an in vitro placental perfusion model, sST2 was secreted by the placenta into the ‘maternal’ eluate, and placental explants treated with pro-inflammatory cytokines or subjected to hypoxia/reperfusion injury release more sST2, suggesting the origin of at least some of the increased amounts of circulating sST2 in pre-eclamptic women is the placenta. These results suggest that sST2 may play a significant role in pregnancies complicated by pre-eclampsia and increased sST2 could contribute to the type 1 bias seen in this disorder.

Variance in total levels of phospholipase C zeta (PLC-ζ) in human sperm may limit the applicability of quantitative immunofluorescent analysis as a diagnostic indicator of oocyte activation capability

OBJECTIVE To examine whether similar levels of phospholipase C zeta (PLC-ζ) protein are present in sperm from men whose ejaculates resulted in normal oocyte activation, and to examine whether a predominant pattern of PLC-ζ localization is linked to normal oocyte activation ability. DESIGN Laboratory study. SETTING University laboratory. PATIENT(S) Control subjects (men with proven oocyte activation capacity; n = 16) and men whose sperm resulted in recurrent intracytoplasmic sperm injection failure (oocyte activation deficient [OAD]; n = 5). INTERVENTION(S) Quantitative immunofluorescent analysis of PLC-ζ protein in human sperm. MAIN OUTCOME MEASURE(S) Total levels of PLC-ζ fluorescence, proportions of sperm exhibiting PLC-ζ immunoreactivity, and proportions of PLC-ζ localization patterns in sperm from control and OAD men. RESULT(S) Sperm from control subjects presented a significantly higher proportion of sperm exhibiting PLC-ζ immunofluorescence compared with infertile men diagnosed with OAD (82.6% and 27.4%, respectively). Total levels of PLC-ζ in sperm from individual control and OAD patients exhibited significant variance, with sperm from 10 out of 16 (62.5%) exhibiting levels similar to OAD samples. Predominant PLC-ζ localization patterns varied between control and OAD samples with no predictable or consistent pattern. CONCLUSION(S) The results indicate that sperm from control men exhibited significant variance in total levels of PLC-ζ protein, as well as significant variance in the predominant localization pattern. Such variance may hinder the diagnostic application of quantitative PLC-ζ immunofluorescent analysis.

Do women with ovaries of polycystic morphology without any other features of PCOS benefit from short-term metformin co-treatment during IVF? A double-blind, placebo-controlled, randomized trial

BACKGROUND Women with ovaries of polycystic morphology (PCO), without any other features of polycystic ovary syndrome (PCOS), respond similarly to women with PCOS when stimulated with exogenous gonadotrophins, and both groups share various endocrinological disturbances underlying their pathology. In women with PCOS, metformin co-treatment during IVF has been shown to increase pregnancy rates and reduce the risk of ovarian hyperstimulation syndrome (OHSS). The aim of this study was to investigate whether metformin co-treatment before and during IVF can also increase the live birth rate (LBR) and lower severe OHSS rates for women with PCO, but no other manifestations of PCOS. METHODS This study was a double-blind, multi-centre, randomized, placebo-controlled trial. The study population included 134 women with ovulatory PCO (and no evidence of clinical or biochemical hyperandrogenism) undergoing IVF treatment at three tertiary referral IVF units. The primary outcome was LBR. RESULTS In total, 134 women were randomized, 69 to metformin and 65 to placebo. There were no statistically significant differences between the two groups in baseline characteristics. With regard to IVF outcome, no significant improvements were found in the metformin group when compared with the placebo group. In particular, there was no difference between the groups in rates of live birth [metformin n = 27 (39.1%), placebo n = 30 (46.2), (95% confidence interval 0.38, 1.49, odds ratio = 0.75)], clinical pregnancy [metformin n = 29 (42.0%), placebo n = 33 (50.8%)] or severe OHSS [metformin n = 6 (8.7%), placebo n = 5 (7.7%)]. CONCLUSIONS There appears to be no benefit in metformin co-treatment before and during IVF in women with PCO without any other features of PCOS. Clinical Trials.gov: NCT01046032.

Motile sperm organelle morphology evaluation-selected globozoospermic human sperm with an acrosomal bud exhibits novel patterns and higher levels of phospholipase C zeta

STUDY QUESTION Does motile sperm organelle morphology examination (MSOME) affect levels and localization patterns of the oocyte activation factor phospholipase C zeta (PLCζ) in globozoospermic sperm with and without an acrosomal bud? SUMMARY ANSWER MSOME identified round-headed globozoospermic sperm with increased levels of PLCζ relative to sperm from the same sample that did not undergo MSOME, and identified novel patterns of PLCζ localization in sperm exhibiting an acrosomal bud. WHAT IS KNOWN ALREADY Absence or reduction in the level of PLCζ in the sperm head, abnormal localization patterning, or defective functional ability as a result of PLCζ gene mutation, have been linked to certain types of human male factor infertility in which oocyte activation is deficient. It has been determined that a subpopulation of sperm (1%) from a patient exhibiting 100% globozoospermia presented with an acrosome bud upon MSOME. A cycle of intracytoplasmic morphologically selected sperm injection, carried out with sperm exhibiting an acrosomal bud led to pregnancy and birth of a healthy baby boy, without the use of assisted oocyte activation (AOA). STUDY DESIGN, SIZE, DURATION Immunofluorescent analysis of PLCζ in globozoospermic sperm from three patients, before and after MSOME. PARTICIPANTS/MATERIALS, SETTING, METHODS Quantitative immunofluorescence was used to investigate PLCζ levels and localization patterns in individual sperm (n = 1 patient) identified by MSOME and isolated by micromanipulation, and presenting with and without the acrosomal bud. A secondary aim was to investigate levels and localization patterns of PLCζ in sperm before and after MSOME from two other globozoospermic men. MAIN RESULTS AND THE ROLE OF CHANCE Non-globozoospermic control sperm exhibited characteristic localization patterns of PLCζ immunofluorescence. Completely round-headed globozoospermic sperm from patients 1-3 were either devoid of PLCζ immunofluorescence, or exhibited an abnormal, punctate, pattern of PLCζ localization. PLCζ immunofluorescence in sperm exhibiting an acrosomal bud was observed in the midpiece with varying fluorescent intensity and was detected in 28.5% of such sperm. The majority of sperm with an acrosomal bud (43.0%) exhibited punctate patterns of PLCζ localization within the sperm head. A further 28.5% of sperm exhibited PLCζ in both the head and the midpiece. Total levels of PLCζ, and the proportions of sperm exhibiting PLCζ immunoreactivity, showed significant variance (P ≤ 0.05) amongst control [45.8 arbitrary units (a.u.) and 95.7%, respectively], non-MSOME-selected (25.9 a.u. and 46.1%, respectively) and MSOME-selected globozoospermic sperm (33.4 a.u. and 65.0%, respectively). Total levels of PLCζ immunofluorescence, and proportions of sperm exhibiting PLCζ immunoreactivity, in control sperm was significantly higher (P≤ 0.05) compared with non-MSOME-selected sperm, but not significantly different from MSOME-selected sperm. LIMITATIONS, REASONS FOR CAUTION The low numbers of sperm analysed may not be ideal for conclusive statistical analysis. Evaluation of the effects of MSOME on morphologically normal sperm would confirm conclusions. WIDER IMPLICATIONS OF THE FINDINGS The present findings provide hope for the future treatment of globozoospermia without the need for AOA, and provide further evidence for the clinical application of PLCζ as a therapeutic and prognostic tool. STUDY FUNDING/COMPETING INTEREST(S) The research described herein was funded by the Nuffield Department of Obstetrics and Gynaecology, University of Oxford. The authors report no conflict of interest.

Intrauterine insemination: a UK survey on the adherence to NICE clinical guidelines by fertility clinics

Objective To evaluate the awareness and response of fertility clinics in the UK to the National Institute for Health and Care Excellence (NICE) guideline recommendation that intrauterine insemination (IUI) should not be offered routinely, in order to report on current practice in the UK. Design Online questionnaire survey of fertility clinics in the UK regarding their current clinical practice of IUI, formal discussion of the guideline recommendations, and any alterations made since the recommendations. Setting 66 UK fertility clinics licensed to provide IUI. Participants 46 fertility clinics, including 6 clinic groups which represent 70% of all clinics and clinic groups licensed to provide IUI in April 2014 when the survey email was sent. Results Of the 46 clinics that responded, 96% (44/46) of clinics continue to offer IUI. 98% (43/44) of those offering IUI also use ovarian stimulation. The most commonly used medications for ovarian stimulation are gonadotrophins (95%), followed by clomiphene citrate (49%) and letrozole (19%). 78% (36/46) of clinics had formally discussed NICE guideline recommendations. 17 clinics (37%) had made some changes to their practices; as a result, four clinics reported a reduction in the number of IUI cycles, six clinics had restricted the indications for IUI, and five clinics had begun informing patients of the guideline recommendations, while two did not specify. Conclusions The majority of clinics were aware of the guideline recommendations. However, only a small proportion of clinics had made significant changes to their practice by reducing the number of IUI cycles or restricting the clinical indications for IUI. The availability of further evidence will assist NICE and clinicians in making recommendations on the use of IUI. There is a need to further explore the reasons for the lack of adherence to the recommendations.

Reproduction and ovarian ageing

Female fertility rates are inherently linked to a womans age, which is in turn related to ovarian function. Reproductive potential declines gradually until 37–38 years of age, from when the rate of decline hastens. Approximately 1% of women suffer from premature ovarian ageing, and many may not have completed their families. This paper reviews the physiology and fertility consequences of ovarian ageing, premature ovarian failure, measures of ovarian reserve and methods of fertility preservation.

Sequential bilateral adnexal torsion after a single cycle of gonadotropin ovulation induction with intrauterine insemination

OBJECTIVE To report a rare case of sequential bilateral adnexal torsion in a pregnant woman after a single cycle of gonadotropin ovulation induction with IUI. To review the literature with regards to the causation and aspects of the management of adnexal torsion, particularly after assisted conception. DESIGN Case report. SETTING Fertility department within a teaching hospital. PATIENT(S) A 35-year-old woman with a twin pregnancy after a cycle of gonadotropin ovulation induction and IUI. INTERVENTION(S) Gonadotropin ovulation induction with IUI; two laparotomies, salpingo-oophorectomy, stabilization of adnexa with stay suture. RESULT(S) Continuation of pregnancy until 37 weeks gestation with the abdominal delivery of healthy twins. CONCLUSION(S) The case of a woman with a multiple pregnancy and ovarian hyperstimulation syndrome after ovulation induction and IUI who developed sequential bilateral adnexal torsion is used to illustrate the risk factors and management options for adnexal torsion. Physicians should be aware of the increased incidence of adnexal torsion in the rising number of women undergoing ovulation induction in order to effect early surgical intervention and adnexal salvage. Consideration should be given to the anchoring of bulky adnexae to prevent torsion recurrence.