In praise of ovulation induction for the management of anovulatory subfertility.

Rapid advances in assisted reproductive technology have revolutionized fertility treatments for couples worldwide seeking a pregnancy. Although this is promising, concerns are emerging over the overuse of unnecessary assisted conception treatments, particularly among couples with anovulatory subfertility. Some experts are calling for the cessation of ovulation induction as the primary treatment of anovulatory subfertility in favour of more sophisticated assisted conception treatments. In the absence of other causes of subfertility, ovulation induction in patients with type 1 and type 2 anovulation disorders can achieve an up to 80% ovulation rate with a 40% cumulative pregnancy rate and few adverse effects. Considering the various risks and high costs associated with assisted reproductive technology treatments, it is hard to argue for their cost-effectiveness when simpler, safer and cheaper pharmacological ovulation induction could achieve comparable pregnancy rates. We argue here for the safe, effective and ethical use of ovulation induction in this population, supplemented by a judicious use of assisted conception treatments. We emphasize the essential role of ovulation induction as a first-line intervention for couples with anovulatory subfertility delivered within a patient-centred multidisciplinary care model and with a clear escalation pathway to use assisted reproductive technology treatments based on the person's response, characteristics and treatment preference.

VEGFA165 can rescue excess steroid secretion, inflammatory markers, and follicle arrest in the ovarian cortex of High A4 cows†.

A population of cows with excess androstenedione (A4; High A4) in follicular fluid, with follicular arrest, granulosa cell dysfunction, and a 17% reduction in calving rate was previously identified. We hypothesized that excess A4 in the ovarian microenvironment caused the follicular arrest in High A4 cows and that vascular endothelial growth factor A would rescue the High A4 phenotype. In trial 1, prior to culture, High A4 ovarian cortex (n = 9) had greater numbers of early stage follicles (primordial) and fewer later-stage follicles compared to controls (n = 11). Culture for 7 days did not relieve this follicular arrest; instead, High A4 ovarian cortex had increased indicators of inflammation, anti-Mullerian hormone, and A4 secretion compared to controls. In trial 2, we tested if vascular endothelial growth factor A isoforms could rescue the High A4 phenotype. High A4 (n = 5) and control (n = 5) ovarian cortex was cultured with (1) PBS, (2) VEGFA165 (50 ng/mL), (3) VEGFA165B (50 ng/mL), or (4) VEGFA165 + VEGFA165B (50 ng/mL each) for 7 days. Follicular progression increased with VEGFA165 in High A4 cows with greater early primary, primary, and secondary follicles than controls. Similar to trial 1, High A4 ovarian cortex secreted greater concentrations of A4 and other steroids and had greater indicators of inflammation compared to controls. However, VEGFA165 rescued steroidogenesis, oxidative stress, and fibrosis. The VEGFA165 and VEGFA165b both reduced IL-13, INFα, and INFß secretion in High A4 cows to control levels. Thus, VEGFA165 may be a potential therapeutic to restore the ovarian steroidogenic microenvironment and may promote folliculogenesis.

Aromatase inhibitors (letrozole) for ovulation induction in infertile women with polycystic ovary syndrome.

BACKGROUND: Polycystic ovary syndrome (PCOS) is the most common cause of infrequent periods (oligomenorrhoea) and absence of periods (amenorrhoea). It affects about 5% to 20% of women worldwide and often leads to anovulatory infertility. Aromatase inhibitors (AIs) are a class of drugs that were introduced for ovulation induction in 2001. Since about 2001 clinical trials have reached differing conclusions as to whether the AI, letrozole, is at least as effective as the first-line treatment clomiphene citrate (CC), a selective oestrogen receptor modulator (SERM). OBJECTIVES: To evaluate the effectiveness and safety of AIs (letrozole) (with or without adjuncts) compared to SERMs (with or without adjuncts) for infertile women with anovulatory PCOS for ovulation induction followed by timed intercourse or intrauterine insemination. SEARCH METHODS: We searched the following sources, from their inception to 4 November 2021, to identify relevant randomised controlled trials (RCTs): the Cochrane Gynaecology and Fertility Group Specialised Register, CENTRAL, MEDLINE, Embase and PsycINFO. We also checked reference lists of relevant trials, searched the trial registers and contacted experts in the field for any additional trials. We did not restrict the searches by language or publication status. SELECTION CRITERIA: We included all RCTs of AIs used alone or with other medical therapies for ovulation induction in women of reproductive age with anovulatory PCOS. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials, extracted the data and assessed risks of bias using RoB 1. We pooled trials where appropriate using a fixed-effect model to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for most outcomes, and risk differences (RDs) for ovarian hyperstimulation syndrome (OHSS). The primary outcomes were live birth rate and OHSS rate. Secondary outcomes were clinical pregnancy, miscarriage and multiple pregnancy rates. We assessed the certainty of the evidence for each comparison using GRADE methods. MAIN RESULTS: This is a substantive update of a previous review; of six previously included trials, we excluded four from this update and moved two to 'awaiting classification' due to concerns about validity of trial data. We included five additional trials for this update that now includes a total of 41 RCTs (6522 women). The AI, letrozole, was used in all trials. Letrozole compared to SERMs with or without adjuncts followed by timed intercourse Live birth rates were higher with letrozole (with or without adjuncts) compared to SERMs followed by timed intercourse (OR 1.72, 95% CI 1.40 to 2.11; I2 = 0%; number needed to treat for an additional beneficial outcome (NNTB) = 10; 11 trials, 2060 participants; high-certainty evidence). This suggests that in women with a 20% chance of live birth using SERMs, the live birth rate in women using letrozole with or without adjuncts would be 27% to 35%. There is high-certainty evidence that OHSS rates are similar with letrozole or SERMs (0.5% in both arms: risk difference (RD) -0.00, 95% CI -0.01 to 0.01; I2 = 0%; 10 trials, 1848 participants; high-certainty evidence). There is evidence for a higher pregnancy rate in favour of letrozole (OR 1.69, 95% CI 1.45 to 1.98; I2 = 0%; NNTB = 10; 23 trials, 3321 participants; high-certainty evidence). This suggests that in women with a 24% chance of clinical pregnancy using SERMs, the clinical pregnancy rate in women using letrozole with or without adjuncts would be 32% to 39%. There is little or no difference between treatment groups in the rate of miscarriage per pregnancy (25% with SERMs versus 24% with letrozole: OR 0.94, 95% CI 0.66 to 1.32; I2 = 0%; 15 trials, 736 participants; high-certainty evidence) and multiple pregnancy rate (2.2% with SERMs versus 1.6% with letrozole: OR 0.74, 95% CI 0.42 to 1.32; I2 = 0%; 14 trials, 2247 participants; high-certainty evidence). However, a funnel plot showed mild asymmetry, indicating that some trials in favour of SERMs might be missing.  Letrozole compared to laparoscopic ovarian drilling (LOD) One trial reported very low-certainty evidence that live birth rates may be higher with letrozole compared to LOD (OR 2.07, 95% CI 0.99 to 4.32; 1 trial, 141 participants; very low-certainty evidence). This suggests that in women with a 22% chance of live birth using LOD with or without adjuncts, the live birth rate in women using letrozole with or without adjuncts would be 24% to 47%. No trial reported OHSS rates. Due to the low-certainty evidence we are uncertain if letrozole improves pregnancy rates compared to LOD (OR 1.47, 95% CI 0.95 to 2.28; I² = 0%; 3 trials, 367 participants; low-certainty evidence). This suggests that in women with a 29% chance of clinical pregnancy using LOD with or without adjuncts, the clinical pregnancy rate in women using letrozole with or without adjuncts would be 28% to 45%. There seems to be no evidence of a difference in miscarriage rates per pregnancy comparing letrozole to LOD (OR 0.65, 95% CI 0.22 to 1.92; I² = 0%; 3 trials, 122 participants; low-certainty evidence). This also applies to multiple pregnancies (OR 3.00, 95% CI 0.12 to 74.90; 1 trial, 141 participants; very low-certainty evidence). AUTHORS' CONCLUSIONS: Letrozole appears to improve live birth rates and pregnancy rates in infertile women with anovulatory PCOS, compared to SERMs, when used for ovulation induction, followed by intercourse. There is high-certainty evidence that OHSS rates are similar with letrozole or SERMs. There was high-certainty evidence of no difference in miscarriage rate and multiple pregnancy rate. We are uncertain if letrozole increases live birth rates compared to LOD. In this update, we added good quality trials and removed trials with concerns over data validity, thereby upgrading the certainty of the evidence base.

Gonadotrophins or clomiphene citrate in women with normogonadotropic anovulation and CC failure: does the endometrium matter?

STUDY QUESTION: Is endometrial thickness (EMT) a biomarker to select between women who should switch to gonadotropins and those who could continue clomiphene citrate (CC) after six failed ovulatory cycles? SUMMARY ANSWER: Using a cut-off of 7 mm for EMT, we can distinguish between women who are better off switching to gonadotropins and those who could continue CC after six earlier failed ovulatory CC cycles. WHAT IS ALREADY KNOWN: For women with normogonadotropic anovulation, CC has been a long-standing first-line treatment in conjunction with intercourse or intrauterine insemination (IUI). We recently showed that a switch to gonadotropins increases the chance of live birth by 11% in these women over continued treatment with CC after six failed ovulatory cycles, at a cost of €15 258 per additional live birth. It is unclear whether EMT can be used to identify women who can continue on CC with similar live birth rates without the extra costs of gonadotropins. STUDY DESIGN, SIZE, DURATION: Between 8 December 2008 and 16 December 2015, 666 women with CC failure were randomly assigned to receive an additional six cycles with a change to gonadotropins (n = 331) or an additional six cycles continuing with CC (n = 335), both in conjunction with intercourse or IUI. The primary outcome was conception leading to live birth within 8 months after randomisation. EMT was measured mid-cycle before randomisation during their sixth ovulatory CC cycle. The EMT was available in 380 women, of whom 190 were allocated to gonadotropins and 190 were allocated to CC. PARTICIPANTS/MATERIALS, SETTING, METHODS: EMT was determined in the sixth CC cycle prior to randomisation. We tested for interaction of EMT with the treatment effect using logistic regression. We performed a spline analysis to evaluate the association of EMT with chance to pregnancy leading to a live birth in the next cycles and to determine the best cut-off point. On the basis of the resulting cut-off point, we calculated the relative risk and 95% CI of live birth for gonadotropins versus CC at EMT values below and above this cut-off point. Finally, we calculated incremental cost-effectiveness ratios (ICER). MAIN RESULTS AND THE ROLE OF CHANCE: Mid-cycle EMT in the sixth cycle interacted with treatment effect (P < 0.01). Spline analyses showed a cut-off point of 7 mm. There were 162 women (45%) who had an EMT ≤ 7 mm in the sixth ovulatory cycle and 218 women (55%) who had an EMT > 7 mm. Among the women with EMT ≤ 7 mm, gonadotropins resulted in a live birth in 44 of 79 women (56%), while CC resulted in a live birth in 28 of 83 women (34%) (RR 1.57, 95% CI 1.13-2.19). Per additional live birth with gonadotropins, the ICER was €9709 (95% CI: €5117 to €25 302). Among the women with EMT > 7 mm, gonadotropins resulted in a live birth in 53 of 111 women (48%) while CC resulted in a live birth in 52 of 107 women (49%) (RR 0.98, 95% CI 0.75-1.29). LIMITATIONS, REASONS FOR CAUTION: This was a post hoc analysis of a randomised controlled trial (RCT) and therefore mid-cycle EMT measurements before randomisation during their sixth ovulatory CC cycle were not available for all included women. WIDER IMPLICATIONS OF THE FINDINGS: In women with six failed ovulatory cycles on CC and an EMT ≤ 7 mm in the sixth cycle, we advise switching to gonadotropins, since it improves live birth rate over continuing treatment with CC at an extra cost of €9709 to achieve one additional live birth. If the EMT > 7 mm, we advise to continue treatment with CC, since live birth rates are similar to those with gonadotropins, without the extra costs. STUDY FUNDING/COMPETING INTEREST(S): The original MOVIN trial received funding from the Dutch Organization for Health Research and Development (ZonMw number: 80-82310-97-12067). C.B.L.A. reports unrestricted grant support from Merck and Ferring. B.W.M. is supported by a NHMRC Practitioner Fellowship (GNT1082548) and reports consultancy for Merck, ObsEva, IGENOMIX and Guerbet. All other authors have nothing to declare. TRIAL REGISTRATION NUMBER: Netherlands Trial Register, number NTR1449.

The cumulative success of ovulation induction therapy with gonadotrophins in therapy-naïve anovulatory women: An observational study.

BACKGROUND: The use of gonadotrophins as a first-line treatment for anovulatory infertility has been limited by a perception of a risk of multi-fetal gestation and ovarian hyperstimulation syndrome (OHSS). However, it has recently been recognised as an acceptable first-line treatment if appropriate monitoring is performed. AIMS: To determine the cumulative live birth rate, incidence of multiple gestation, cycle cancellation rate and incidence of OHSS for therapy-naïve anovulatory women undergoing ovulation induction with gonadotrophins. MATERIALS AND METHODS: A prospective observational study of 258 patients undergoing ovulation induction with a 'low-dose step-up' protocol was performed over a three-year period across two fertility centres (40% of patients were currently or recently prescribed metformin). RESULTS: Twenty-six percent of patients required concurrent use of luteinising hormone. The cumulative pregnancy and live birth rates were 22.5% and 18.2%, 40.3% and 34.5%, 47.7% and 41.1% after completion of the first, second and third cycles of stimulation, respectively, with a median duration of stimulation of 15 days. No patients developed OHSS and 10.5% of cycles were cancelled due to an excessive or no follicular response. The multiple pregnancy rate was 2%. The cumulative pregnancy rate was reduced for women over 35 years of age (23.8 vs 55.3%, P = 0.006) and for women with a body mass index greater than 25 kg/m2 (40.6 vs 56.7%, P = 0.027). CONCLUSIONS: This study demonstrated that ovulation induction with gonadotrophin therapy, in the context of appropriate monitoring, is a safe and effective treatment for young therapy-naïve patients with anovulatory infertility.

EVALUATION OF THE RISK FACTORS OF CERVICAL INSUFFICIENCY IN WOMEN WITH INFERTILITY ASSOCIATED WITH ANOVULATION.

Cervical insufficiency is a common problem in obstetrical care. There are not enough studies about its development in women with infertility. The aim of the article was to determine the risk factors of the development of cervical insufficiency in women with infertility associated with anovulation. The object of the study were 308 pregnant women (110 pregnant women with cervical insufficiency and without infertility, 92 pregnant women with infertility associated with anovulation and with cervical insufficiency, 76 pregnant women with infertility associated with anovulation and without cervical insufficiency, 30 pregnant women without cervical insufficiency and infertility (controls)). We analyzed the data of obstetrical anamnesis, gynecological diseases, extragenital pathology. In fertile women with cervical insufficiency the traumatic factor of the cervix (previous labors, gynecological procedures connected with cervical dilatation) was the main in the development of this pathology. While in the women with infertility associated with anovulation the forming of cervical insufficiency was associated with hormonal reasons (hyperandrogenism (OR=3.04, 95 % CI=1.15-8.05, p=0.03), diminished ovarian reserve (OR=6.00, 95 % CI=1.97-18.24, p=0.002), controlled ovarian stimulation with gonadotropin and clomiphene citrate use (OR=3.69, 95% CI=1.93-7.04, p<0.001), use of additional reproductive technology (OR=1.95, 95 % CI=1.05-3.63, p=0.03).

Gonadotrophins versus clomiphene citrate with or without IUI in women with normogonadotropic anovulation and clomiphene failure: a cost-effectiveness analysis.

STUDY QUESTION: Are six cycles of ovulation induction with gonadotrophins more cost-effective than six cycles of ovulation induction with clomiphene citrate (CC) with or without IUI in normogonadotropic anovulatory women not pregnant after six ovulatory cycles with CC? SUMMARY ANSWER: Both gonadotrophins and IUI are more expensive when compared with CC and intercourse, and gonadotrophins are more effective than CC. WHAT IS KNOWN ALREADY: In women with normogonadotropic anovulation who ovulate but do not conceive after six cycles with CC, medication is usually switched to gonadotrophins, with or without IUI. The cost-effectiveness of these changes in policy is unknown. STUDY DESIGN, SIZE, DURATION: We performed an economic evaluation of ovulation induction with gonadotrophins compared with CC with or without IUI in a two-by-two factorial multicentre randomized controlled trial in normogonadotropic anovulatory women not pregnant after six ovulatory cycles with CC. Between December 2008 and December 2015 women were allocated to six cycles with gonadotrophins plus IUI, six cycles with gonadotrophins plus intercourse, six cycles with CC plus IUI or six cycles with CC plus intercourse. The primary outcome was conception leading to a live birth achieved within 8 months of randomization. PARTICIPANTS/MATERIALS, SETTING, METHODS: We performed a cost-effectiveness analysis on direct medical costs. We calculated the direct medical costs of ovulation induction with gonadotrophins versus CC and of IUI versus intercourse in six subsequent cycles. We included costs of medication, cycle monitoring, interventions, and pregnancy leading to live birth. Resource use was collected from the case report forms and unit costs were derived from various sources. We calculated incremental cost-effectiveness ratios (ICER) for gonadotrophins compared to CC and for IUI compared to intercourse. We used non-parametric bootstrap resampling to investigate the effect of uncertainty in our estimates. The analysis was performed according to the intention-to-treat principle. MAIN RESULTS AND THE ROLE OF CHANCE: We allocated 666 women in total to gonadotrophins and IUI (n = 166), gonadotrophins and intercourse (n = 165), CC and IUI (n = 163), or CC and intercourse (n = 172). Mean direct medical costs per woman receiving gonadotrophins or CC were €4495 versus €3006 (cost difference of €1475 (95% CI: €1457-€1493)). Live birth rates were 52% in women allocated to gonadotrophins and 41% in those allocated to CC (relative risk (RR) 1.24:95% CI: 1.05-1.46). The ICER was €15 258 (95% CI: €8721 to €63 654) per additional live birth with gonadotrophins. Mean direct medical costs per woman allocated to IUI or intercourse were €4497 versus €3005 (cost difference of €1510 (95% CI: €1492-€1529)). Live birth rates were 49% in women allocated to IUI and 43% in those allocated to intercourse (RR = 1.14:95% CI: 0.97-1.35). The ICER was €24 361 (95% CI: €-11 290 to €85 172) per additional live birth with IUI. LIMITATIONS, REASONS FOR CAUTION: We allowed participating hospitals to use their local protocols for ovulation induction and IUI, which may have led to variation in costs, but which increases generalizability. Indirect costs generated by transportation or productivity loss were not included. We did not evaluate letrozole, which is potentially more effective than CC. WIDER IMPLICATIONS OF THE FINDINGS: Gonadotrophins are more effective, but more expensive than CC, therefore, the use of gonadotrophins in women with normogonadotropic anovulation who have not conceived after six ovulatory CC cycles depends on society's willingness to pay for an additional child. In view of the uncertainty around the cost-effectiveness estimate of IUI, these data are not sufficient to make recommendations on the use of IUI in these women. In countries where ovulation induction regimens are reimbursed, policy makers and health care professionals may use our results in their guidelines. STUDY FUNDING/COMPETING INTEREST(S): This trial was funded by the Netherlands Organization for Health Research and Development (ZonMw number: 80-82310-97-12067). The Eudract number for this trial is 2008-006171-73. The Sponsor's Protocol Code Number is P08-40. CBLA reports unrestricted grant support from Merck and Ferring. BWM is supported by a NHMRC Practitioner Fellowship (GNT1082548) and reports consultancy for Merck, ObsEva and Guerbet. TRIAL REGISTRATION NUMBER: NTR1449.

Ovulation induction: comparing success rates between anovulatory and ovulatory cycles using different treatment protocols.

The management of patients with sub-fertility, particularly unexplained sub-fertility, is a sensitive and complex matter. This was a prospective observational study conducted from October 2016 to March 2017 in Galway, Ireland, the aim of which was to identify the clinical pregnancy rates (CPR) in women undergoing ovulation induction (OI) with timed sexual intercourse (TSI) or intrauterine insemination (IUI) and to compare them across two groups: (1) Anovulatory women and (2) ovulatory women with unexplained subfertility. Patients undergoing OI were recruited consecutively and OI regimens were prescribed as per local clinical protocol. The main observation was a higher CPR in the anovulatory group (18%) compared with the ovulatory group (CPR = 10%) (p < 0.05). No difference was observed in the CPR between the TSI and IUI groups. There are many studies to support the use of OI in the treatment of women with anovulatory subfertility, though the use of OI in ovulatory women is a more controversial issue. The treatment options offered to these patients need to be individualized to each couple and should consider their length of infertility, age, and financial means. Due to the lower cost and the less invasive nature of OI-treatment we conclude that a short treatment course could be offered as an acceptable alternative prior to IVF.

Basal Anti Mullerian hormone levels and endometrial thickness at midcycle can predict the outcome after clomiphene citrate stimulation in anovulatory women with PCOS, a retrospective study.

PURPOSE: Recent studies reported that in polycystic ovary syndrome (PCOS) patients, other stimulation agents are superior to the popular first-line regimen, clomiphene citrate (CC) for ovarian stimulation. Nonetheless, CC is still widely used since it is not clear which patients will not respond to it. Furthermore, the prognostic value of endometrium thickness at midcycle is controversial. We aimed to find factors predicting the response to CC and the prognostic value of endometrial thickness at midcycle. METHODS: We collected data retrospectively from 89 anovulatory PCOS patients who had the first stimulation with 50 mg CC. We analyzed the basal levels of AMH, testosterone, LH, LH:FSH ratio and the endometrial thickness at midcycle by univariate, followed by multivariate regression. The outcome measures were pregnancy, follicle maturation and endometrial thickness at midcycle. RESULTS: Stimulation with 50 mg CC resulted in follicle maturation in 50.6% of the women and in 27.0% pregnancies. In the univariate analysis, greater endometrial thickness, lower LH and AMH levels and a lower LH:FSH ratio were associated with pregnancy (p < 0.05). In the multivariate analysis, only endometrial thickness remained predictive (p = 0.045). The endometrial thickness cutoff level of ≥ 8 mm showed a sensitivity of 87.5% (96% CI 67.6-97.3) and a specificity of 66.7% (95% CI 43.0-85.4) for prediction of pregnancy. In the multivariate analysis AMH levels 5.4 (3.4; 7.0) (ng/mL) predicted pregnancy (ß = - 0.194 ± 0.092; p = 0.034) CONCLUSION: We suggest to refrain from CC as first-line regimen in patients with AMH > 7 ng/ml. Under CC treatment, the cutoff value of ≥ 8 mm endometrium thickness at midcycle is associated with a better outcome.

Low-dose gonadotropin induction of ovulation in anovulatory women: still needed in the age of IVF.

Low-dose, step-up gonadotropin is the treatment of choice for women with polycystic ovary syndrome (PCOS) who have not conceived after anti-oestrogen treatment and as an effective alternative to pulsatile GnRH in women with hypogonadotropic hypogonadism (HH). There has been, however, no large-scale, comparative study between the two groups using low-dose gonadotropins. Here, we performed a retrospective, comparative analysis, in a single clinic database, of efficacy and safety of induction of ovulation using low-dose gonadotropins in 364 women with PCOS and 80 women with HH. The rate of ovulation was high in both PCOS (83%) and HH (84%) but mono-follicular, ovulatory cycles were more prevalent in PCOS than in HH (77% vs 53%, P < 0.0001) and the proportion of cycles that were abandoned was higher in HH than in PCOS (25% vs 15%, P < 0.0001). The median threshold dose of gonadotropin required to induce ovulation was 75 IU/day in PCOS and 113 IU/day in HH (P < 0.001) and the range of doses was greater in HH women. Forty-nine percent of women with PCOS and 65% of those with HH conceived (more than 90% within 6 cycles of treatment) and had at least one pregnancy. Multiple pregnancies (all twins) occurred in only 4% of women with PCOS and 5% of those with HH. These findings emphasise the efficacy and safety of low-dose gonadotropin treatment for both clomiphene-resistant women with PCOS and those with HH. These results highlight the importance of choosing the more physiological approach of gonadotropin induction of ovulation in both groups as the most appropriate treatment, in preference to IVF.

Inositol treatment of anovulation in women with polycystic ovary syndrome: a meta-analysis of randomised trials.

Polycystic ovary syndrome is a common cause of anovulation and infertility, and a risk factor for development of metabolic syndrome and endometrial cancer. Systematic review and meta-analysis of randomised controlled trials (RCT) that evaluated the effects of inositol as an ovulation induction agent. We searched MEDLINE, EMBASE, Cochrane and ISI conference proceedings, Register and Meta-register for RCT and WHO trials' search portal. We included studies that compared inositol with placebo or other ovulation induction agents. Quality of studies was assessed for risk of bias. Results were pooled using random effects meta-analysis and findings were reported as relative risk or standardised mean differences. We included ten randomised trials. A total of 362 women were on inositol (257 on myo-inositol; 105 on di-chiro-inositol), 179 were on placebo and 60 were on metformin. Inositol was associated with significantly improved ovulation rate (RR 2.3; 95% CI 1.1-4.7; I2 = 75%) and increased frequency of menstrual cycles (RR 6.8; 95% CI 2.8-16.6; I2 = 0%) compared with placebo. One study reported on clinical pregnancy rate with inositol compared with placebo (RR 3.3; 95% CI 0.4-27.1), and one study compared with metformin (RR 1.5; 95% CI 0.7-3.1). No studies evaluated live birth and miscarriage rates. Inositol appears to regulate menstrual cycles, improve ovulation and induce metabolic changes in polycystic ovary syndrome; however, evidence is lacking for pregnancy, miscarriage or live birth. A further, well-designed multicentre trial to address this issue to provide robust evidence of benefit is warranted. TWEETABLE ABSTRACT: Inositols improve menstrual cycles, ovulation and metabolic changes in polycystic ovary syndrome.

Effect of clomiphene citrate on endometrial thickness, ovulation, pregnancy and live birth in anovulatory women: systematic review and meta-analysis.

OBJECTIVES: To compare the impact of clomiphene citrate (CC) vs other drug regimens on mid-cycle endometrial thickness (EMT), ovulation, pregnancy and live birth rates in women with World Health Organization (WHO) group II ovulatory disorders. METHODS: We searched MEDLINE, EMBASE, Scopus, Web of Science, The Cochrane Central Register of Clinical Trials (CENTRAL) and the non-MEDLINE subset of PubMed from inception to December 2016 and cross-checked references of relevant articles. We included only randomized controlled trials (RCTs) comparing CC used alone vs other drug regimens for ovulation induction in women with WHO group II anovulation. Outcomes were mid-cycle EMT, ovulation, pregnancy and live birth rates. We pooled weighted mean differences (WMD) with 95% confidence intervals (CI) for continuous variables (EMT) and risk ratios (RR) with 95% CI for binary variables (ovulation, pregnancy and live birth rates). RESULTS: We retrieved 1718 articles of which 33 RCTs (4349 women, 7210 ovulation induction cycles) were included. In 15 RCTs that compared CC with letrozole, EMT was lower in the CC group (1957 women, 3892 cycles; WMD, -1.39; 95% CI, -2.27 to -0.51; I2 = 100%), ovulation rates after CC and letrozole were comparable (1710 women, 3217 cycles; RR, 0.97; 95% CI, 0.90-1.04; I2 = 47%), while CC led to a lower pregnancy rate (1957 women, 3892 cycles; RR, 0.78; 95% CI, 0.63-0.95; I2 = 43%) and a lower live birth rate (RR, 0.70; 95% CI, 0.49-0.98; I2 = 35%). In two RCTs that compared CC with CC plus metformin, EMT, ovulation and pregnancy rates were comparable (101 women, 140 cycles; WMD, -0.23; 95% CI, -0.92 to 0.45; I2 = 78%; RR, 0.84; 95% CI, 0.67-1.06; I2 = 0%; and RR, 0.79; 95% CI, 0.33-1.87; I2 = 0%). In three studies that compared CC with CC plus N-acetyl cysteine (NAC), EMT was lower in the CC group (340 women, 300 cycles; WMD, -1.51; 95% CI, -1.98 to -1.04; I2 = 45%). In two studies that compared CC with CC + nitric oxide (NO) donor, EMT was lower in the CC group (120 women, 304 cycles; WMD, -1.75; 95% CI, -2.08 to -1.41; I2 = 0%). Compared with CC plus NO donor or NAC, CC showed statistically significant lower ovulation and pregnancy rates. Compared with tamoxifen in three studies, CC showed a tendency towards lower EMT (571 women, 844 cycles; WMD, -1.34; 95% CI, -2.70 to 0.01; I2 = 96%) with comparable ovulation and pregnancy rates. CONCLUSIONS: In women with WHO group II ovulatory disorders, ovulation induction with CC might result in lower EMT than other ovulation induction regimens. Whether the lower EMT caused the lower pregnancy and live birth rates remains to be elucidated. Letrozole seems to be beneficial for these women. However, our findings should be interpreted with caution as the quality of evidence was very low. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Therapeutic approach for metabolic disorders and infertility in women with PCOS.

Polycystic ovary syndrome (PCOS) is a complex endocrine disorder affecting 5-10% of women of reproductive age. It generally shows with oligo/amenorrhea, anovulatory cycles, clinical o biochemical hirsutism, polycystic ovaries and, in a significant percentage of cases, insulin resistance. PCOS is defined as a multifactorial pathology, determined by the association of many factors: genetic, endocrine and environmental. The first and most effective treatment of PCOS is to change life-style and lose weight. The use of oral contraceptives has been shown effective in reducing acne and hirsutism and regulates the menstrual cycle. For women with severe hirsutism, the addition of antiandrogens to estrogen-progestin therapy has significantly improved the results. In cases of anovulatory infertility, the drug of first choice is clomiphene citrate, followed by low-dose gonadotropins. Recently, insulin-sensitizing drugs have been widely prescribed for PCOS patients. They are particularly effective in reducing insulin resistance and improving ovulatory performance. Besides insulin-sensitizing drugs, natural substances, such as inositol, seems to have good efficacy, similar to metformin with fewer side effects. New substances that could be used include statins and natural statins, such as monakolin, alone or combined with myo-inositol. These substances do not have side effects and greatly reduce the hyperandrogenic component in these patients.

Low dose HP-hMG in an antagonist protocol for IVF in ovulatory and anovulatory patients with high AMH.

Women with high-AMH levels have an increased risk of ovarian hyperstimulation syndrome (OHSS). Studies have suggested that highly purified menotropin (HP-hMG) Menopur® reduces the risk. We, therefore, studied use of low-dose (112.5 IU/day) HP-hMG in ovulatory and anovulatory patients with high AMH (>32 pmol/L). The primary endpoint was the distribution of patients with appropriate, excessive, and inadequate response (5-14, ≥15, and ≤4 oocytes). Another endpoint was frequency of OHSS. Totally 115 women were included and 78 (67.8%) had an appropriate, 8 (7.0%) an excessive, and 29 (25.2%) an inadequate response. The number of oocytes was independent on AMH levels and ovulatory status but declined significantly with increasing bodyweight (R2 = 0.07, p < .01). The ongoing pregnancy rate per started cycle was 47.0%. Three (2.6%) developed OHSS, two had cancelation of the cycle and seven patients had GnRH agonist triggering to prevent OHSS. Selective use of a low dose of HP-hMG in patients with high levels of AMH provides 5-14 oocytes in more than two-thirds of the patients and is safe with low risk of OHSS. The number of aspirated oocytes was independent of AMH levels and ovulatory status, but inversely related to body weight.

Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility.

BACKGROUND: Polycystic ovary syndrome (PCOS) is characterised by infrequent or absent ovulation, and high levels of androgens and insulin (hyperinsulinaemia). Hyperinsulinaemia occurs secondary to insulin resistance and is associated with increased risk of cardiovascular disease and diabetes mellitus. Insulin-sensitising agents such as metformin may be effective in treating PCOS-related anovulation. OBJECTIVES: To evaluate the effectiveness and safety of insulin-sensitising drugs in improving reproductive and metabolic outcomes for women with PCOS undergoing ovulation induction. SEARCH METHODS: We searched the following databases from inception to January 2017: Cochrane Gynaecology and Fertility Group Specialised Register, CENTRAL, MEDLINE, Embase, PsycINFO and CINAHL. We searched registers of ongoing trials and reference lists from relevant studies. SELECTION CRITERIA: We included randomised controlled trials of insulin-sensitising drugs compared with placebo, no treatment, or an ovulation-induction agent for women with oligo and anovulatory PCOS. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for eligibility and bias. Primary outcomes were live birth rate and gastrointestinal adverse effects. Secondary outcomes included other pregnancy outcomes, menstrual frequency and metabolic effects. We combined data to calculate pooled odds ratios (ORs) and 95% confidence intervals (CIs). We assessed statistical heterogeneity using the I2 statistic and reported quality of the evidence for primary outcomes using GRADE methodology. MAIN RESULTS: We assessed the interventions metformin, clomiphene citrate, metformin plus clomiphene citrate, D-chiro-inositol, rosiglitazone and pioglitazone. We compared these with each other, placebo or no treatment. We included 48 studies (4451 women), 42 of which investigated metformin (4024 women). Evidence quality ranged from very low to moderate. Limitations were risk of bias (poor reporting of methodology and incomplete outcome data), imprecision and inconsistency. Metformin versus placebo or no treatmentThe evidence suggests that metformin may improve live birth rates compared with placebo (OR 1.59, 95% CI 1.00 to 2.51, 4 studies, 435 women, I2 = 0%, low-quality evidence). The metformin group experienced more gastrointestinal side effects (OR 4.76, 95% CI 3.06 to 7.41, 7 studies, 670 women, I2 = 61%, moderate-quality evidence) but had higher rates of clinical pregnancy (OR 1.93, 95% CI 1.42 to 2.64, 9 studies, 1027 women, I2 = 43%, moderate-quality evidence), ovulation (OR 2.55, 95% CI 1.81 to 3.59, 14 studies, 701 women, I2 = 58%, moderate-quality evidence) and menstrual frequency (OR 1.72, 95% CI 1.14 to 2.61, 7 studies, 427 women, I2 = 54%, low-quality evidence). There was no clear evidence of a difference in miscarriage rates (OR 1.08, 95% CI 0.50 to 2.35, 4 studies, 748 women, I2 = 0%, low-quality evidence). Metformin plus clomiphene citrate versus clomiphene citrate alone There was no conclusive evidence of a difference between the groups in live birth rates (OR 1.21, 95% CI 0.92 to 1.59, 9 studies, 1079 women, I2 = 20%, low-quality evidence), but gastrointestinal side effects were more common with combined therapy (OR 3.97, 95% CI 2.59 to 6.08, 3 studies, 591 women, I2 = 47%, moderate-quality evidence). However, the combined therapy group had higher rates of clinical pregnancy (OR 1.59, 95% CI 1.27 to 1.99, 16 studies, 1529 women, I2 = 33%, moderate-quality evidence) and ovulation (OR 1.57, 95% CI 1.28 to 1.92, 21 studies, 1624 women, I2 = 64%, moderate-quality evidence). There was a statistically significant difference in miscarriage rate per woman, with higher rates in the combined therapy group (OR 1.59, 95% CI 1.03 to 2.46, 9 studies, 1096 women, I2 = 0%, low-quality evidence) but this is of uncertain clinical significance due to low-quality evidence, and no clear difference between groups when we analysed miscarriage per pregnancy (OR 1.30, 95% CI 0.80 to 2.12, 8 studies; 400 pregnancies, I2 = 0%, low-quality evidence). Metformin versus clomiphene citrateWhen all studies were combined, findings for live birth were inconclusive and inconsistent (OR 0.71, 95% CI 0.49 to 1.01, 5 studies, 741 women, I2 = 86%, very low-quality evidence). In subgroup analysis by obesity status, obese women had a lower birth rate in the metformin group (OR 0.30, 95% CI 0.17 to 0.52, 2 studies, 500 women, I2 = 0%, very low-quality evidence), while data from the non-obese group showed a possible benefit from metformin, with high heterogeneity (OR 1.71, 95% CI 1.00 to 2.94, 3 studies, 241 women, I2 = 78%, very low-quality evidence). Similarly, among obese women taking metformin there were lower rates of clinical pregnancy (OR 0.34, 95% CI 0.21 to 0.55, 2 studies, 500 women, I2 = 0%, very low-quality evidence) and ovulation (OR 0.29, 95% CI 0.20 to 0.43 2 studies, 500 women, I2 = 0%, low-quality evidence) while among non-obese women, the metformin group had more pregnancies (OR 1.56, 95% CI 1.05 to 2.33, 5 studies, 490 women, I2 = 41%, very low-quality evidence) and no clear difference in ovulation rates (OR 0.81, 95% CI 0.51 to 1.28, 4 studies, 312 women, low-quality evidence, I2=0%). There was no clear evidence of a difference in miscarriage rates (overall: OR 0.92, 95% CI 0.50 to 1.67, 5 studies, 741 women, I2 = 52%, very low-quality evidence). D-chiro-inositol (2 studies), rosiglitazone (1 study) or pioglitazone (1 study) versus placebo or no treatmentWe were unable to draw conclusions regarding other insulin-sensitising drugs as no studies reported primary outcomes. AUTHORS' CONCLUSIONS: Our updated review suggests that metformin alone may be beneficial over placebo for live birth, although the evidence quality was low. When metformin was compared with clomiphene citrate, data for live birth were inconclusive, and our findings were limited by lack of evidence. Results differed by body mass index (BMI), emphasising the importance of stratifying results by BMI. An improvement in clinical pregnancy and ovulation suggests that clomiphene citrate remains preferable to metformin for ovulation induction in obese women with PCOS.An improved clinical pregnancy and ovulation rate with metformin and clomiphene citrate versus clomiphene citrate alone suggests that combined therapy may be useful although we do not know whether this translates into increased live births. Women taking metformin alone or with combined therapy should be advised that there is no evidence of increased miscarriages, but gastrointestinal side effects are more likely.

Extension of the clomiphene citrate stair-step protocol to gonadotropin treatment in women with clomiphene resistant polycystic ovarian syndrome.

Our objective was to evaluate the safety and efficacy of direct initiation of gonadotropin ovarian stimulation without prior withdrawal bleeding in anovulatory clomiphene citrate (CC) resistant polycystic ovarian syndrome (PCOS) patients. Eighteen PCOS patients underwent ovulation induction with CC using a stair-step regimen. Patients who failed to respond to the maximal dose of CC initiated gonadotropin stimulation without inducing withdrawal bleeding, using the chronic low dose regimen. The primary outcome measure was the time to ovulation from the beginning of CC treatment until the day of ovulatory trigger. This was compared with the time to ovulation calculated according to the traditional approach, which includes inducing progesterone withdrawal bleeding between each CC dose increment and before gonadotropin therapy. The time to ovulation in the study group was 67.0 ± 6.8 days. The estimated time to ovulation according to the traditional approach was approximately 110 days. The clinical pregnancy rate was 44% (8/18), and all pregnancies were singletons. One patient miscarried; hence the live birth rate was 38.9% (7/18). Direct initiation of gonadotropin therapy without prior induction of withdrawal bleeding in clomiphene resistant PCOS patients results in considerable reduction of the time to ovulation and is both safe and efficacious.

Influence of the conclusion of a recent large cooperative study in changing standard protocol of inducing menses in anovulatory women with oligomenorrhea prior to initiating ovulation induction with anti-estrogens and outcome.

PURPOSE: To compare pregnancy rates following ovulation induction in anovulatory women with clomiphene citrate vs. letrozole and to determine the relative confounding effect of inducing menses or not. The study also evaluated whether starting these anti-estrogen drugs later in the menstrual cycle has-less adverse effect on endometrial thickness. MATERIALS AND METHODS: Prospective series with choice by physician of inducing menses or not or choosing clomiphene citrate or letrozole for ovulation induction. Peak endometrial thickness was compared between drugs and between those conceiving or not. RESULTS: There were 21 first cycles using letrozole and 42 using clomiphene. Menses were not induced in 18/21 (86%) letrozole cycles and 24/42 (57%) clomiphene cycles. Clinical pregnancies occurred in four (22.2%) letrozole cycles without induced menses with one miscarriage vs. 4/24 (16.6%) clomiphene cycles, no mis- carriage. One of three (33.3%) letrozole cycles with menses induced achieved a clinical pregnancy vs. only 1/18 (5.5%) of clomiphene cycles. There were no miscarriages. CONCLUSIONS: Though the endometrial thickness was higher with clomiphene without induced menses vs. menses induced (11 mm vs. 9.5 mm), one cannot explain the trend for lower pregnancy rates in women with induced menses because of thinner endometria since the thickness was 10.3 mm for clomiphene and 10.0 with letrozole.

[Features of Professor Ma Kun's medication in treating ovulatory infertility].

In order to analyze Professor Ma Kun's medication in treating anovulatory infertility, her prescriptions for treating anovulatory infertility in 2012-2015 were collected. The medication features and the regularity of prescriptions were mined by using traditional Chinese medicine inheritance support system, association rules, complex system entropy clustering and other mining methods. Finally, a total of 684 prescriptions and 300 kinds of herbs were screened out, with a total frequency of 11 156 times; And 68 core combinations and 8 new prescriptions were mined. The top three frequently used herbs by effect were respectively tonic herb, blood circulation promoting herb, and Qi-circulation promoting herb. The top three tastes were sweetness, bitterness and pungent flavor. The results showed 28 herbs with a high frequency of ≥100.The top 10 frequently used herbs were respectively Angelica Sinensis Radix, Cyperi Rhizoma, Chuanxiong Rhizome, Paeoniae Radix Rubra, Cyathulae Radix, Taxilli Herba, Cuscutae Semen, Codonopsis Radix, Ligustri Lucidi Fructus, Paeoniae Albaand Paeoniae Radix Alba. The association rules analysis showed commonly used herbal pairs, including Rehmanniae Radix Preparata-Chuanxiong Rhizome, Rehmanniae Radix Preparata-Angelica Sinensis Radix, Cuscutae Semen-Dipsaci Radix. In conclusion, Professor Ma has treated anovulatory infertility by nourishing the kidney and activating blood throughout the treatment course, and attached the importance to the relationship between Qi and blood and there gulation of liver, spleen and kidney in treating anovulatory infertility.

[Study on the mechanism of Bushen Culuan Chongji treating "kidney deficiency and blood stasis" in ovulatory dysfunctional infertility].

Kidney deficiency and blood stasis is the main cause of ovulatory dysfunctional infertility. Kidney deficiency is the main pathological mechanism. Blood stasis is the main pathological manifestation, and it is an important factor throughout. Bushen Culuan Chongji is under the guidance of traditional Chinese medicine(TCM) theory, previous years of clinical experience, combined with the etiology and pathogenesis of anovulatory infertility and modern pharmacological research results, selected, not only maintains the TCM syndrome differentiation and different diseases features, but also reflects the superiority of the combination of disease. In the study of Bushen Culuan Chongji in the treatment of anovulatory infertility, there was no acute toxicity and no LD50 was detected. No adverse effects and side effects were found in the reproductive, genetic, toxicity, teratogenic, and perinatal tests in their high and low dose groups. In pharmacodynamics experiments, it can promote the development and maturation of follicles and the formation of corpus luteum in rats. Taking the kidney deficiency and blood stasis syndrome as the breakthrough point, systematically study the efficacy, safety and mechanism of six ovulatory dysfunctional infertility diseases, including abnormal uterine bleeding-ovulatory disorders, polycystic ovary syndrome, high prolactin, luteinized unruptured follicle syndrome, luteal phase defect and diminished ovarian reserve/premature ovarian failure. It verified the contribution degree of reinforcing kidney and resolving stasis TCM, reflected the characteristics of combination between disease differentiation and syndrome differentiation, interpreted the treatment principles of treating different diseases with the same method, and provided scientific basis for clinical treatment.

[Treatment of anovulatory infertility by tonifying kidney and promoting blood circulation].

Infertility is a common disease in women of childbearing age and is also a refractory disease. Anovulatory dysfunction is one of the main causes of female infertility, and the incidence of anovulatory infertility has been increasing year by year. Traditional Chinese medicine has unique advantages and definite curative effect on the treatment of this disease. Kidney deficiency is the basic pathogenesis and blood stasis is an important factor that has been through. Flexible of tonifying the kidney and promoting blood circulation treatment of anovulatory infertility in clinic, has achieved remarkable curative effect. Kidney deficiency and blood stasis is a common form of gynecological disease. After years of clinical practice, we also found that patients with anovulatory infertility were more common with kidney deficiency and blood stasis. The kidneys and blood are not isolated from each other, but interact and influence each other. Kidney deficiency and blood stasis interact as both cause and effect, they have very close relationship. To achieve the purpose of urinary Tiangui, Chongren, ovulation and pregnancy miscarriage by tonifying the kidney and promoting blood circulation.