Gillian M. Lockwood

Circulating inhibins and activin A during GnRH‐analogue down‐regulation and ovarian hyperstimulation with recombinant FSH for in‐vitro fertilization‐embryo transfer

OBJECTIVE We have investigated serial changes in plasma concentrations of inhibin A, inhibin B, pro αC and activin A in women undergoing stimulation with recombinant FSH in ‘long‐protocol’ down‐regulated cycles of IVF treatment.

Successful pregnancy outcome in a renal transplant patient following in-vitro fertilization

Renal transplantation transforms the fertility potential of women with end-stage renal failure and the prognosis for both pregnancy outcome and continuing renal function in those patients is generally good. Currently one in 50 women become pregnant following renal transplant and it may be assumed that more would welcome the chance of biological parenthood if their fertility problems, related often to tubal damage, could be overcome. We here report our experience of treating a couple with secondary infertility with in-vitro fertilization and embryo transfer where the wife is a renal transplant recipient. We believe this is the first reported case.

The role of inhibin in polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is a common heterogeneous disorder which, in its severest manifestations, is associated with anovulation, hyperandrogenism and metabolic imbalance. The biochemical markers for the condition can include a significantly raised LH:FSH ratio and a raised testosterone concentration, indicating a derangement of the hypothalamo-pituitary-ovarian axis which may be primary or secondary to a primary ovarian pathology. The bioactive inhibins are heterodimeric glycoproteins consisting of α-βA (inhibin A) and α-βB (inhibin B) subunits. They play an endocrine role in co-regulating (with oestradiol) the suppression of FSH during the late follicular and luteal phases of the ovarian cycle and they are implicated in intraovarian paracrine signalling. Inhibin B, which is the predominant form in small pre-ovulatory follicles, increases in concentration from early in the follicular phase to reach a peak coincident with the onset of the decrease in FSH which forms the basis of the pattern of mono-ovulation seen in normoovulatory women. Several unique features of the dysovulation of women with PCOS, namely their failure to recruit and develop a dominant follicle despite having ‘normal’ concentrations of endogenous FHS, the raised LH:FSH ratio and their exquisite sensitivity to exogenous FSH injections, may be explained by their significantly higher inhibin B concentrations. Studies into inhibin B parameters in women with PCOS demonstrate that women with anovular PCOS have significantly higher concentrations of circulating inhibin B and that they lack the pulsatile pattern of secretion that can be detected in normo-ovulatory women during the mid-follicular phase. The inhibin B response to ovulation induction with clomiphene citrate in women with PCOS differs from that in normo-ovulatory women taking the anti-oestrogen. Women with PCOS who over-respond to ovulation induction with injected FSH in a ‘low-dose’ step-up protocol’ and recruit multiple follicles have significantly higher concentrations of pre-treatment inhibin B than PCOS subjects who do not.

Having it all? Where are we with "social" egg freezing today?

It is 30 years since the first successful “frozen egg” pregnancy was conceived (Chen, 1986) and the difficulty and delay in reliably replicating Chen’s original breakthrough was for many years the reason that oocyte cryopreservation was rightly considered to be a low-chance option for fertility preservation or extension. Early estimates suggested that 100 eggs were needed to get one live birth. For young women facing the near inevitable sterility of chemotherapy or radiotherapy, the prospect of freezing their eggs, if they were not in a relationship where embryo creation and cryopreservation was an option, even a low chance of genetic motherhood was acceptable. The introduction of new cryoprotectants that improved the freeze-thaw survival rates, and ICSI, which improved the fertilization rates, were welcome, but it was not until vitrification was applied to oocytes that the situation of egg freezing was transformed. Nowadays, it is probable that ovarian cortex freezing represents a superior and speedier option for cancer patients (ASRM Practice Committee, 2014) but this approach is not widely available. Therehavebeen twoEuropeandevelopments in recent years that have given the field of oocyte cryopreservation an unexpected boost. During the period when Italian law required all embryos created in a fresh cycle to be transferred and embryo cryopreservation was not allowed (Benagiano et al., 2014), there was intense pressure to improve the pregnancy rates from the supernumerary oocytes that could neither be fertilised nor transferred. These frozen-thawed oocytesmade a valuable contribution to the cumulative pregnancy rate in Italy and demonstrated that “stopping the biological clock” for older would-be mothers could give them the opportunity of healthy pregnancies at an advanced age. The second development involving frozen eggs is the ascendancy of Spain as the principal provider of donor eggs to European women with age-related subfertility (Ahuja, 2015). Several excellent Spanish clinics now have “frozen egg banks” where young, vitrified, quarantined eggs are available to match any racial or physical characteristic required by the recipients. The pregnancy rates from these donor eggs, obtained from young women, are strictly comparable with those from fresh egg donation cycles. The success of these programmes has inevitably lead to increased enthusiasm for autologous egg freezing – not because of a deliberate intention to delay childbearing by the majority of highly-educated, professional women who seek eggfreezing – but because they want to have the opportunity to become a mother in a supportive, long-term relationship (Smajdor, 2015). In a paper in this issue of RBMOnline, Kylie Baldwin and colleagues (Baldwin et al., 2015) confirm findings from studies in the US and Europe that absence of a partner is the commonest reason for “social” egg freezing, although anxiety about having a less than optimal reproductive “life-span” due to family or gynaecological history may also be relevant. The announcement by Facebook and Apple that they would cover the costs of “social” egg-freezing for their female employees has re-ignited the debate about whether egg-freezing represents the ultimate type of “family planning” for today’s professional woman or whether the prospect of having 15 cryopreserved metaphase II oocytes in the freezer (the minimum number recommended) really does offer the opportunity to safely defer and delay motherhood until the right time arrives or the perfect partner hoves into view. However, the majority of women choosing to freeze their eggs have unfortunately already left it too late to have a realistic chance of achieving a live-birth from a single cycle of egg freezing (Everywoman, 2013). Just as with “fresh” eggs, successful pregnancies are more likely to be obtained using frozen young eggs – the early miscarriage rate from pregnancies achieved from older frozen eggs seems to be even higher than that of spontaneous pregnancies or “fresh” egg cycles of older women (Ubaldi et al., 2010). The circumstances in which women choose to egg freeze often reflect their social situation, in which they have either failed to find a partner who wishes to parent with them, or a long-term relationship that they assumed was heading towards parenthood has failed, often because of commitment issues. It is unfair and unfortunate that at 38 (the modal age at which UK women seek egg freezing), she has two years to realistically achieve a healthy pregnancy whereas her similarly-aged partner has two decades. Baldwin and

Comparison of highly purified FSH (Metrodin-High Purity) with Pergonal for IVF superovulation

AbstractPurpose: The use of highly purified follicle-stimulating hormone (Metrodin-HP) was compared with that of a preparation containing follicle-stimulating hormone and luteinizing hormone (Pergonal) for production of superovulation in an IVF program. Methods: We used the Oxford Fertility Unit database to identify patients undergoing their first cycle of IVF, using either Metrodin-HP or Pergonal. Patients were treated with a standardized drug protocol and were stratified by age and cause of infertility. Ovarian stimulation with either Metrodin-HP (Serono Laboratories) or human menopausal gonadotropin (hMG; Pergonal; Serono Laboratories) after pituitary desensitization commenced in the midluteal phase of the preceding cycle. Monitoring was performed by ultrasound and serum estradiol measurement prior to transvaginal oocyte recovery, followed by IVF and transfer of no more than three embryos. Results: For Metrodin-HP versus Pergonal, the rates of egg retrieval (98 vs 94%), fertilization (89 vs 92%), clinical pregnancy (32.9 vs 23.4%), miscarriage (4.1 vs 4.5%), live birth (26 vs 18.5%), and ovarian hyperstimulation syndrome (5.5% vs 5.9%) were similar in both groups. The apparent increase in clinical pregnancy and live birth with Metrodin-HP did not reach statistical significance. The dosages of gonadotropins used were comparable. Estradiol levels measured on day 8 of stimulation were significantly lower in the Metrodin-HP group than in the Pergonal group, but the difference did not reach statistical significance on the day of hCG administration. Significantly more follicles (greater than 12 mm) were obtained in the Metrodin-HP group, but the numbers of eggs recovered and fertilized were similar in the two groups. Conclusions: These findings demonstrate that highly purified FSH (Metrodin-HP) is as effective and successful as hMG (Pergonal) for ovarian stimulation in a standard IVF regimen. Exogenous luteinizing hormone (LH) is not required for satisfactory ovarian stimulation in IVF. Measurement of estradiol may be less helpful in the monitoring of Metrodin-HP cycles, but the level reached on the day of hCG administration can still be used to predict, and hence avoid, ovarian hyperstimulation syndrome.

Successful transvaginal ultrasound-guided ablation of a cervical pregnancy in a patient with simultaneous intrauterine pregnancy after in vitro fertilization and embryo transfer

Heterotopic pregnancy, or simultaneous intrauterine and extrauterine gestation, is a relatively rare condition. However, induced ovulation and assisted reproductive technologies have markedly increased the incidence of this condition. In this article, a case of heterotopic pregnancy after in vitro fertilization and embryo transfer is presented in which the viable cervical pregnancy was treated by transvaginal ultrasound-guided puncture and injection of potassium chloride in conjunction with methotrexate at week 6 of gestation. At week 12 of gestation, the intrauterine gestation was viable and complete resorption of the cervical pregnancy had occurred. At week 30 of gestation, a healthy baby was delivered by Caesarian section after prelabour rupture of membranes.

Retrospective comparison of GnRH agonist trigger with HCG trigger in GnRH antagonist cycles in anticipated high-responders

All IVF-ICSI cycles carried out between October 2009 and October 2012 using GnRH agonist (GnRHa) ovulation trigger (n = 62) followed by a single dose of HCG plus progesterone and oestradiol in the luteal phase because of anticipated ovarian hypertsimulation were retrospectively compared with historic control cycles using HCG trigger (n = 29) and standard luteal phase support. Womens mean age, body mass index, anti-Müllerian hormone, FSH, LH, starting and total stimulation dose, number of follicles, oocytes, embryos, fertilization, implantation, polycystic ovary syndrome, ICSI, live birth and ongoing pregnancy rates per embryo transfer were similar (GnRHa 40.7% versus HCG 35.0%). For each started cycle, GnRHa resulted in 11.4% higher (statistically non-significant) live birth and ongoing pregnancy rate (OR 1.73, CI 0.64 to 4.69), with a similar difference for double-embryo transfers (OR 1.62, CI 0.44 to 6.38) and less need for freezing all embryos (9.7% versus 27.6%; P = 0.04). Incidence of mild-to-moderate OHSS was 16.2% with GnRHa trigger and 31.0% with HCG trigger) and no severe OHSS in the former. The addition of single low-dose HCG in the luteal phase after GnRHa trigger for suspected high-responders reduced the incidence of OHSS with good clinical outcomes, compared with HCG trigger.

A randomized controlled trial comparing the efficacy and safety of two HMG preparations gaining their LH bioactivity from different HCG sources

In this prospective, controlled, randomized, multicentre, non-inferiority study, efficacy and safety of two HMG preparations (Menopur®- Ferring and Meriofert®- IBSA Institut Biochimique SA) for ovarian stimulation were compared (270 women undergoing IVF aged between 18 and 39 years; BMI 30 kg/m2 or less; less than three prior completed assisted reproduction technique cycles). A standard long down-regulation with gonadotrophin-releasing hormone agonist protocol, with HCG triggering was used; primary end-point was total number of oocytes retrieved; attention was paid toovarian hyperstimulation syndrome (OHSS). No statistically significant differences between the treatment groups were reported for most of the clinically significant end-points, including embryo quality, fertilization rate, implantation rate, ongoing pregnancy rate and live birth rate. Total number of oocytes retrieved was higher in the new HMG group compared with the reference (11.6 ± 6.6 and 9.7 ± 5.9, respectively, with a 95% CI of the difference equal +0.43 to +3.43). Increased number of oocytes was obtained through a shorter stimulation, but HMG units per oocyte retrieved were equivalent. The safety profile of the products for frequency of ovarian hyperstimulation syndrome was the same. This study showed that the new HMG preparation is a viable alternative for conducting ovarian stimulation in IVF cycles.

Can we predict the chance of successful epididymal or testicular sperm aspiration following vasectomy

Abstract Purpose of this retrospective study was to investigate if serum markers, men’s age, interval since vasectomy, BMI, testicular size and smoking could predict the success of epididymal or testicular sperm aspiration (PESA/TESA) in vasectomized men. Forty-four consecutively performed PESA/TESA procedures were reviewed retrospectively. Motile sperm was retrieved from 77.3% of PESA/TESA procedures. Mean serum Inhibin-B (Inh-B) level tended to be higher in men who had motile sperm retrieved compared to those who had not (180.3 versus 126.2 pg/ml, p = 0.05). Univariate analysis identified serum Inh-B to be the only predictor of PESA/TESA success (r = 0.32, CI: 0.006–0.584, p = 0.046). Serum FSH, LH, T levels, age, BMI, smoking status and interval since vasectomy did not correlate with the PESA/TESA outcome. Inh-B could modestly discriminate between successful and unsuccessful PESA/TESA (AUC= 0.70) with high positive (89.5%) but low negative prediction (36.8%); 58.6% sensitivity and 77.7% specificity at the optimum cut-off level of 166 pg/ml. Positive outcome was only 50% when the Inh-B level was below 100 pg/ml. It is concluded that a high serum Inh-B might reliably predict successful PESA/TESA in vasectomized men. More invasive sperm retrieval procedures could be reserved for men with very low Inh-B or failed PESA/TESA. Future studies with adequate power may confirm our findings.