R. Homburg

Oocyte vitrification—Women's emancipation set in stone

The techniques of vitrification of oocytes and the subsequent warming process being used today are now producing results far superior to the results that are obtained with slow-freezing techniques, and it would seem that this is the method of female fertility preservation that will be widely used in the near future. The reported success of the use of this method should stimulate a renewed debate on oocyte storage for fertility preservation without a medical indication.

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

BACKGROUNDnClomifene 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.nnnMETHODSnInfertile 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.nnnRESULTSnPatients (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.nnnCONCLUSIONSnPregnancies 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.

Clomiphene citrate resistance in relation to follicle-stimulating hormone receptor Ser680Ser-polymorphism in polycystic ovary syndrome

BACKGROUNDnClomiphene citrate (CC) response in anovulatory women is difficult to predict and patient-tailored treatment would benefit patient care and time-management. The objective of this study was to evaluate the role of the follicle-stimulating hormone receptor (FSHR) Ser680Ser-polymorphism as a predictor for CC response.nnnMETHODSnIn this retrospective study, 193 patients, diagnosed with polycystic ovary syndrome (PCOS) according to Rotterdam criteria and treated with ovulation induction, were included over a 5-year period in a university hospital in the Netherlands. Data on demographics, BMI, menstrual cycle, laboratory screening (including FSHR genotyping), transvaginal ultrasonography of ovaries and ovulation parameters were collected. Main outcome measures were response to CC and FSHR genotype.nnnRESULTSnThe frequency distribution of the 680-polymorphism was 26% (Asn/Asn), 50% (Asn/Ser) and 24% (Ser/Ser). No significant differences in basal characteristics were found. Significantly more patients with Ser/Ser-polymorphism were resistant to CC (28%) compared with Asn/Ser (14%) and Asn/Asn group (15%), with an odds ratio for ovulation of 0.44 (95% CI, 0.21-0.97). Patients with higher FSH levels, higher age and lower BMI were significantly more likely to ovulate in univariate analysis. In a multivariate logistic regression model, corrected for age, BMI, mean ovarian, volume, hyperandrogenism, and amenorrhoea, only FSHR and basal FSH levels were predictive for ovulation.nnnCONCLUSIONSnChance of resistance to CC is almost double in women with PCOS harbouring the Ser/Ser genotype.

Microvascular function has no menstrual-cycle-dependent variation in healthy ovulatory women

Objective: Hyper‐ and hypoestrogenism that persist for a long time can affect vascular and metabolic function. However, it is not clear whether the same is true for subtle sex hormone changes (i.e., during the menstrual cycle).

LH as a diagnostic criterion for polycystic ovary syndrome in patients with WHO II oligo/amenorrhoea

Elevated LH is common in polycystic ovary syndrome (PCOS), but is not part of the diagnostic criteria. LH concentrations are usually assessed in the early follicular phase when it is suppressed, and therefore the prevalence is underestimated. In this study, LH is measured during the specific oligomenorrhoeic phase, when LH is least suppressed, and its importance as a diagnostic tool for PCOS is evaluated. Patients presenting with oligo- or amenorrhoea between 2002 and 2006 were selected, with the exclusion of women with WHO III oligoamenorrhoea, hyperprolactinaemia or with wrongly timed endocrine measurements. A total of 252 patients were included (198 oligo/amenorrhoeic PCOS patients and 54 oligo/amenorrhoeic controls). Mean LH concentrations were higher in PCOS patients than in controls (11.0 versus 4.1 IU/l, P < 0.001). The receiver operating characteristics (ROC) curve showed an optimal cut-off for LH of > or =6.5 IU/l, resulting in a sensitivity of 84%, specificity of 78% and a likelihood ratio of 3.8, and elevated LH concentrations predicted PCOS accurately in 93%. In conclusion, elevated LH concentrations are found in a large majority of PCOS patients when measured at the appropriate time, and could be used as an additional diagnostic test to differentiate between oligo/amenorrhoeic PCOS patients and other causes of oligo- or anovulation.

Recombinant LH supplementation to a standard GnRH antagonist protocol in women of 35 years or older undergoing IVF/ICSI: a randomized controlled multicentre study

STUDY QUESTIONnDoes the addition of exogenous LH to an IVF/ICSI stimulation protocol with recombinant FSH (r-FSH) and a GnRH antagonist improve the ovarian response and pregnancy rates in women of 35 years and older?nnnSUMMARY ANSWERnSupplementation of LH during the second half of the follicular phase has no effect on pregnancy rates, implantation rates or on ovarian response in women of 35 years and older undergoing GnRH antagonist IVF/ICSI cycles.nnnWHAT IS KNOWN ALREADYnIn IVF/ICSI stimulation protocols GnRH agonists or antagonists are administered to prevent a premature pituitary LH surge, which can have a detrimental effect on the IVF/ICSI procedure. In effect, GnRH analogues cause the levels of both gonadotrophins to drop. In order to allow follicle growth FSH is administered exogenously, whereas LH is usually not supplemented. Although GnRH analogues prevent LH surges, there is evidence that, particularly in older women, administration of GnRH analogues may cause endogenous LH levels to decrease excessively. Several studies have been performed to investigate whether the addition of recombinant LH (r-LH) to r-FSH improves cycle outcome. Only a few studies have analysed this issue in the GnRH antagonist protocol and the results of these trials obtained in older women (>35 years old) are conflicting.nnnSTUDY DESIGN, SIZE, DURATIONnA multicentre RCT was performed between 2004 and 2010 in 253 couples who were undergoing IVF or ICSI. Women were 35 years or older and received ovarian stimulation in a protocol with r-FSH (Gonal-F 225 IU/day) starting from cycle day 3 and GnRH antagonist (Cetrotide 0.25 mg/day) from stimulation day 6. Randomization took place on stimulation day 6 to receive both r-FSH and r-LH (Luveris 150 IU/day) or continue with FSH alone. Randomization for r-LH supplementation was performed centrally by serially numbered, opaque, sealed envelopes, stratified by centre.nnnPARTICIPANTS/MATERIALS, SETTING, METHODSnOf 253 subjects randomized, 125 received both r-FSH and r-LH and 128 received r-FSH only. Patients were recruited from the Division of Reproductive Medicine of the Obstetrics and Gynaecology department of four hospitals in the Netherlands.nnnMAIN RESULTS AND THE ROLE OF CHANCEnThere were no demographic or clinical differences between the groups. The intention-to-treat analysis revealed that of those receiving both r-FSH and r-LH, 35 (28.0%) had a clinical pregnancy, compared with 38 (29.7%) receiving only r-FSH (mean difference -1.5%; 95% confidence interval (CI) -9.4 to 12.7, P = 0.9). Ongoing pregnancy rates were 25 (20%) versus 28 (21.9%) (mean difference -1.9%; 95% CI -8.2 to 11.9, P = 0.9) and implantation rates 18.8 versus 20.7% (mean difference -1.9%; 95% CI -8.0 to 11.7, P = 0.6) in the r-FSH and r-LH and r-FSH only groups respectively.nnnLIMITATIONS, REASONS FOR CAUTIONnA limitation of our study is its early closure. This was done because the interim analysis after randomization of 250 patients indicated no benefit in any aspect of the experiment.nnnWIDER IMPLICATIONS OF THE FINDINGSnGiven previous data, including a Cochrane review, and our own results the evidence indicates that LH supplementation has no benefit on ongoing pregnancy rates in women of 35 years or older.nnnSTUDY FUNDING/COMPETING INTEREST(S)nMerck Serono Netherlands, an affiliate of Merck Serono SA- Geneva, an affiliate of Merck KGaA, Darmstadt, Germany has donated the r-LH (Luveris(®)). No conflict of interest to declare.nnnTRIAL REGISTRATION NUMBERnThe trial was registered in the Dutch trial register (ISRCTN10841210).

Extensive tissue damage of bovine ovaries after bipolar ovarian drilling compared to monopolar electrocoagulation or carbon dioxide laser

OBJECTIVEnTo evaluate the size of ovarian damage caused by ovarian drilling in polycystic ovary syndrome, the amount of inflicted damage was assessed for the most frequently used ovarian drilling techniques.nnnDESIGNnExperimental prospective design.nnnSETTINGnUniversity clinic.nnnPATIENT(S)nSix fresh bovine ovaries per technique.nnnINTERVENTION(S)nCarbon dioxide (CO(2)) laser, monopolar electrocoagulation, and bipolar electrocoagulation were used for in vitro ovarian drilling.nnnMAIN OUTCOME MEASURE(S)nAmount of inflicted ovarian damage per procedure.nnnRESULT(S)nBipolar electrocoagulation resulted in significantly more destruction per burn than the CO(2) laser and monopolar electrocoagulation (287.6 versus 24.0 and 70.0 mm(3), respectively). The damage found per lesion was multiplied by the regularly applied number of punctures per procedure in daily practice (based on the literature). Again, the bipolar electrocoagulation resulted in significantly more tissue damage than the CO(2) laser and monopolar coagulation (2,876 versus 599 and 700 mm(3), respectively).nnnCONCLUSION(S)nOvarian drilling, especially bipolar electrocoagulation, causes extensive destruction of the ovary. Given the same clinical effectiveness of the various procedures, it is essential to use the lowest possible dose that works; thus, the first choice should be CO(2) laser or monopolar electrocoagulation.

GnRH antagonist versus long agonist protocols in IVF: a systematic review and meta-analysis accounting for patient type

BACKGROUNDnMost reviews of IVF ovarian stimulation protocols have insufficiently accounted for various patient populations, such as ovulatory women, women with polycystic ovary syndrome (PCOS) or women with poor ovarian response, and have included studies in which the agonist or antagonist was not the only variable between the compared study arms.nnnOBJECTIVE AND RATIONALEnThe aim of the current study was to compare GnRH antagonist protocols versus standard long agonist protocols in couples undergoing IVF or ICSI, while accounting for various patient populations and treatment schedules.nnnSEARCH METHODSnThe Cochrane Menstrual Disorders and Subfertility Review Group specialized register of controlled trials and Pubmed and Embase databases were searched from inception until June 2016. Eligible trials were those that compared GnRH antagonist protocols and standard long GnRH agonist protocols in couples undergoing IVF or ICSI. The primary outcome was ongoing pregnancy rate. Secondary outcomes were: live birth rate, clinical pregnancy rate, number of oocytes retrieved and safety with regard to ovarian hyperstimulation syndrome (OHSS). Separate comparisons were performed for the general IVF population, women with PCOS and women with poor ovarian response. Pre-planned subgroup analyses were performed for various antagonist treatment schedules.nnnOUTCOMESnWe included 50 studies. Of these, 34 studies reported on general IVF patients, 10 studies reported on PCOS patients and 6 studies reported on poor responders. In general IVF patients, ongoing pregnancy rate was significantly lower in the antagonist group compared with the agonist group (RR 0.89, 95% CI 0.82-0.96). In women with PCOS and in women with poor ovarian response, there was no evidence of a difference in ongoing pregnancy between the antagonist and agonist groups (RR 0.97, 95% CI 0.84-1.11 and RR 0.87, 95% CI 0.65-1.17, respectively). Subgroup analyses for various antagonist treatment schedules compared to the long protocol GnRH agonist showed a significantly lower ongoing pregnancy rate when the oral hormonal programming pill (OHP) pretreatment was combined with a flexible protocol (RR 0.74, 95% CI 0.59-0.91) while without OHP, the RR was 0.84, 95% CI 0.71-1.0. Subgroup analysis for the fixed antagonist schedule demonstrated no evidence of a significant difference with or without OHP (RR 0.94, 95% CI 0.79-1.12 and RR 0.94, 95% CI 0.83-1.05, respectively). Antagonists resulted in significantly lower OHSS rates both in the general IVF patients and in women with PCOS (RR 0.63, 95% CI 0.50-0.81 and RR 0.53, 95% CI 0.30-0.95, respectively). No data on OHSS was available from trials in poor responders.nnnWIDER IMPLICATIONSnIn a general IVF population, GnRH antagonists are associated with lower ongoing pregnancy rates when compared to long protocol agonists, but also with lower OHSS rates. Within this population, antagonist treatment prevents one case of OHSS in 40 patients but results in one less ongoing pregnancy out of every 28 women treated. Thus standard use of the long GnRH agonist treatment is perhaps still the approach of choice for prevention of premature luteinization. In couples with PCOS and poor responders, GnRH antagonists do not seem to compromise ongoing pregnancy rates and are associated with less OHSS and therefore could be considered as standard treatment.

Serial uterine artery Doppler velocity parameters and human uterine receptivity in IVF/ICSI cycles

To evaluate the predictive value of serial uterine artery Doppler ultrasound for embryo implantation in in‐vitro fertilization (IVF)‐intracytoplasmic sperm injection (ICSI) cycles.

Mass spectrometry methods measured androgen and estrogen concentrations during pregnancy and in newborns of mothers with polycystic ovary syndrome

OBJECTIVEnLittle is known about the aetiology of polycystic ovary syndrome (PCOS). Some suggest that elevated maternal androgens during gestation play a causative role. This implies placental passage of androgens during pregnancy. The aim of this study is to compare androgen and estrogen concentrations in maternal serum during pregnancy and in umbilical cord blood, between mothers with PCOS and their offspring compared to controls.nnnDESIGNnProspective case-control study.nnnMETHODSnMaternal blood samples were collected around 20 weeks of gestation and at delivery. Umbilical cord blood was also taken at delivery. Androgens (testosterone (T), androstenedione (ADION), dehydroepiandrostenedione (DHEA)) and estrogens (estrone (E1), estradiol (E2), estriol (E3)) were measured using the liquid chromatography tandem mass spectrometry (LC-MS/MS) methods.nnnRESULTSnAt 20 weeks of gestation: T (P=0.019) and ADION (P=0.034) were higher in the PCOS mothers (pregnant with a girl), whereas DHEA, E1, E2, and E3 were not different. Maternal concentration at birth: T (P=0.004) and ADION (P=0.009) were also higher in the subgroup of PCOS mothers that were pregnant with a girl compared to the girl pregnancy controls. DHEA, E1, E2 and E3 were not different. In umbilical cord blood, no differences were found for T, ADION, DHEA, E2, E3, and AMH between the PCOS mothers and the controls respectively. E1 was lower in girls from PCOS mothers (P=0.007).nnnCONCLUSIONSnDespite elevated maternal androgen concentrations during pregnancy in PCOS mothers, offspring showed no signs of elevated androgen concentrations in cord blood at birth using the latest highly specific LC-MS/MS methods.