Multifollicular Development Research Articles

Pregnancy outcomes after superovulation-intrauterine insemination (SO-IUI) using gonadotropins versus letrozole in the obese population.

To compare fertilityoutcomes of obese patients (body mass index [BMI] ≥ 30kg/m2) undergoing superovulation and intrauterine insemination (SO-IUI) using gonadotropins versus letrozole. A single centre retrospective cohort study of obese patients undergoing SO-IUI using gonadotropins or letrozole between January/2019 and June/2022. Primary outcome was clinical pregnancy rate (intrauterine pregnancy with positive fetal heart rate). Secondary outcomes included rates of multifollicular development, multiple pregnancy, spontaneous abortion and cycle cancellation. Subgroup analysis was done stratifying by obesity class. A multivariate logistic regression model was used for primary/secondary outcomes, adjusting for clinically determined covariates. Out of 802 total identified SO-IUI cycles, 715 cycles were completed (518-gonadotropins and 197-letrozole cycles). The clinical pregnancy rates were not significantly different in obese patients undergoing SO-IUI with gonadotropins versus letrozole when adjusted for age, gravidity, parity, cause of infertility, IUI cycle number, endometrial thickness, sperm source and post-wash motile sperm count (adjusted odds ratio [aOR] 1.37, 95% confidence interval [CI] 0.72-2.59). Similarly, no significant associations were found in spontaneous abortion (aOR1.46, 95%CI 0.42-5.08), multiple pregnancy (aOR1.33, 95%CI 0.20-8.88) or cancellation rates (OR0.89, 95%CI 0.55-1.45) between the two groups. The rates of multifollicular development were also comparablebetweenthe two groups (aOR0.51, 95% CI 0.19-1.38). For cycles involving gonadotropins, higher BMI classes required higher total gonadotropin dose (p < 0.001). After adjusting for patient and cycle factors, gonadotropins and letrozole led to comparable odds of achieving pregnancy in obese patients undergoing SO-IUI. Future research in the obese population will help to better understand how to optimize fertility treatments for this growing population.

A comparison of letrozole regimens for ovulation induction in women with polycystic ovary syndrome

To determine the optimal letrozole regimen for ovulation induction (OI) in women with polycystic ovary syndrome (PCOS). Retrospective cohort study. Single academic fertility clinic from 2015-2022. A total of 189 OI cycles in 52 patients with PCOS. Patients were prescribed 1 of 4 letrozole regimens (group 1: 2.5 mg for 5 days, group 2: 2.5 mg for 10 days, group 3: 5 mg for 5 days, and group 4: 5 mg for 10 days). The primary outcome was ovulation, and secondary outcomes included multifollicular development, and clinical pregnancy rate, which were analyzed with binary logistic regression. Kaplan-Meier cumulative response curves and a Cox proportional hazard regression model were used for time-dependent analyses. Mean age was 30.9 years (standard deviation [SD], 3.6) and body mass index was 32.1 kg/m2 (SD, 4.0). Group 2 (odds ratio [OR], 9.12; 95% confidence interval [CI], 1.92-43.25), group 3 (OR, 3.40; 95% CI, 1.57-7.37), and group 4 (OR, 5.94; 95% CI, 2.48-14.23) had improved ovulation rates after the starting regimen as compared with group 1. Cumulative ovulation rates exceeded 84% in all groups, yet those who received 5 mg and/or 10 days achieved ovulation significantly sooner. Multifollicular development was not increased in groups 2-4 as compared with group 1. Groups 2-4 also demonstrated improved time to pregnancy. Ovulation rates are improved when starting with letrozole at 5 mg and/or a 10-day extended course as compared with the frequently-used 2.5 mg for 5 days. This may shorten time to ovulation and pregnancy.

Ideal frozen embryo transfer regime.

This review aims to compare evidence on four criteria (embryo implantation, obstetric outcomes, patient convenience, and IVF-unit efficiency) by analyzing published research on different endometrial preparation methods for frozen embryo transfer (FET). While the artificial-FET cycle provides advantages in scheduling and implantation, it falls short in ensuring optimal obstetric outcomes. In contrast, natural-FET ensures embryo implantation conditions if ovulation is correctly identified. Supplementing with exogenous progesterone shields against low corpus luteum progesterone secretion, crucial for positive obstetric outcomes. In mNC-FET, ovulation is hCG-triggered, closely resembling natural cycles and reducing monitoring visits for enhanced patient convenience.Letrozole is a recommended option for anovulatory patients, preserving endometrial thickness. It is cost-effective, less likely to induce multifollicular development than gonadotropins, and better tolerated.In a novel approach, the natural-proliferative-phase-FET initiates progesterone in an unmediated ovulatory cycle at 7 mm endometrial thickness, combining the benefits of a natural proliferative endometrium with the convenience of scheduled artificial cycles. The artificial cycle offers scheduling advantages, but may compromise obstetric outcomes. Natural FET relies on accurate ovulation timing for successful implantation. mNC-FET simplifies the process using hCG induction, minimizing clinic visits for improved convenience. Letrozole is highlighted as a cost-effective and well tolerated option in anovulatory patients. A recent innovative approach combines elements of natural and artificial cycles, showing promise for FET procedures.

Individualised gonadotropin dose selection using markers of ovarian reserve for women undergoing in vitro fertilisation plus intracytoplasmic sperm injection (IVF/ICSI).

Individualised gonadotropin dose selection using markers of ovarian reserve for women undergoing in vitro fertilisation plus intracytoplasmic sperm injection (IVF/ICSI).

#226 : Comparison of Letrozole vs Letrozole Plus Metformin as First Line Ovulation Induction Drug for Infertile PCOS Women

Background: Letrozole is currently considered as first line ovulation induction drug in anovulatory PCOS women. Insulin sensitizers like Metformin have a proven role as an adjuvant to improve ovulatory function in resistant PCOS women. Letrozole and Metformin combined as first line ovulation induction option has not been studied much, neither has been compared to other options. Objective: The aim of this study was to compare Letrozole plus Metformin vs Letrozole alone as first line ovulation induction drug in treatment naive infertile PCOS women. Materials &amp; Methods: 125 PCOS patients with anovulatory infertility were randomized by a computer generated randomization list to receive either Letrozole 5 mg from day 3-7 of menses plus Metformin daily (65 patients,150 cycles, Group I) or Letrozole 5mg/day from day 3-7 (60 patients, 121 cycles, Group II). The primary outcome studied was live birth rates and the secondary outcomes reported were ovulation rate, mono / multifollicular development, endometrial thickness, pregnancy rates, abortion and twinning rates. Results: Live birth rate was 33.8% in group I and 45.8% in group II (p=0.17) which was not statistically significantly different. The ovaluation rate was 85.9% and 86.7% (P=0.85) respectively. Multi follicular ovulation was slightly more in Group 2 (38.6% vs 48.1%). Conclusion: There was no significant benefit of adding Metformin to Letrozole as first line ovulation induction drug in terms of live birth rate or ovulation rates.

The importance of infertility duration and follicle size according to pregnancy success in women undergoing ovulation induction with gonadotropins and intrauterine insemination

In this study, we aimed to evaluate the effect of infertility duration and dominant follicle size measured on the day of human chorionic gonadotropin (HCG) administration on pregnancy rates in infertile women undergoing ovulation induction (OI) with gonadotropin (GND). A total of 352 patients aged 20 to 41 years who were diagnosed with unexplained infertility or polycystic ovary syndrome (PCOS) were included in this study. Patients with a history of multifollicular development or follicle stimulating hormone (FSH) value more than 12 IU/ml were excluded from the study. The demographic and clinical features of the patients were obtained from the patients’ files and hospital automation system and recorded for each woman. The demographic and clinical features of the patients were recorded. Patients were divided into two groups as live birth (group 1, n = 47) and non-live birth groups (group 2, n = 305). There were no statistically significant differences in regard to age, infertility type, follicle stimulating hormone (FSH) level, oestradiol (E2) level, antral follicle count (AFC), cycle characteristics, GND type, number of follicles, E2 level and endometrial thickness on HCG day, total GND dose, dominant follicle size (p > 0.05). Infertility duration in group 1 was 3.5 ± 2.1; in group 2, 4.7 ± 3.9 years. This difference was statistically significant (p = .014). According to this study, live birth rates after GND + IUIs(intrauterine insemination) were significantly affected by the duration of infertility. But the dominant follicle size and endometrial thickness measured on HCG day in GND and IUI cycles did not have a significant effect on pregnancy rates. IMPACT STATEMENT What is already known on the subject? It is thought that the timing of the ovarian triggering is vital for the success of intrauterine insemmination (IUI) treatment. What do the results of this study add? According to our results live birth rates after GND + IUIs were significantly affected by the duration of infertility. What are the implications of these findings for clinical practice and/or further research? It is determined that the duration of infertility is significant and patients should be encouraged to the treatment as soon as possible.

AN INTERPRETABLE AND GENERALIZABLE MACHINE LEARNING MODEL FOR OPTIMIZING DAY OF TRIGGER DURING OVARIAN STIMULATION

The goal of ovarian stimulation during in vitro fertilization (IVF) is to promote multifollicular development in order to retrieve multiple high-quality eggs. One of the most important decisions during this process is the timing of the trigger injection. Triggering too early may prevent eggs from reaching maturity, while triggering too late may result in post-mature eggs and risk of hyperstimulation. Machine learning models can support in making this decision, but should be interpretable so the basis for their recommendations are understood, and generalizable to perform well on data from different clinics.

Luteal phase support with progesterone does not improve pregnancy rates in patients undergoing ovarian stimulation with letrozole

Research questionDoes luteal phase support with vaginal progesterone improve clinical pregnancy rates in patients undergoing ovarian stimulation with letrozole? DesignThis was a retrospective cohort study of patients undergoing ovarian stimulation with letrozole paired with intrauterine insemination (IUI) or timed intercourse (TIC) from January 2018 to October 2021. The primary outcome of clinical pregnancy rate (CPR) was calculated for cycles with and without luteal phase progesterone support. Univariate logistic regressions were done to evaluate predictor variables for CPR. Clinically important covariates including age, body mass index, anti-Müllerian hormone concentration, diagnosis of ovulatory dysfunction and multifollicular development were included in a multivariate analysis evaluating the relationship between luteal progesterone use and odds of clinical pregnancy. Secondary outcomes including spontaneous abortion, biochemical pregnancy and ectopic pregnancy were calculated. Live birth rates were calculated for cycles in a secondary analysis. ResultsA total of 492 letrozole ovarian stimulation cycles in 273 patients were included. Of these cycles, 387 (78.7%) used vaginal progesterone for luteal support and 105 (21.3%) did not. The unadjusted CPR per cycle was 11.6% (45/387) with progesterone and 13.3% (14/105) without progesterone (P = 0.645). After adjusting for significant covariates including age, BMI, diagnosis of ovulatory dysfunction and multifollicular development, the odds for clinical pregnancy were not significantly improved in cycles with exogenous progesterone (odds ratio [OR] 1.15, 95% confidence interval [CI] 0.48–2.75, P = 0.762). A follow-up analysis demonstrated that live birth rate was 10.7% (41/384) with and 12.5% (13/104) without luteal progesterone, respectively (P = 0.599). ConclusionsLuteal support with vaginal progesterone does not significantly improve CPR in ovarian stimulation cycles using letrozole.

P-568 The effect of recombinant hCG on FSH-induced ovarian stimulation in rats depends on the FSH dose and can be detrimental at high concentrations

Abstract Study question What is the effect of choriogonadotropin beta (CG beta) on FSH-induced ovarian stimulation and multifollicular development in a rat model? Summary answer CG beta dose-dependently potentiates effects of low-to-mid FSH doses but has inhibitory effects at high concentrations: optimal CG beta/FSH ratio depends on the FSH dose. What is known already Similarly to follitropin delta (rFSH), CG beta (FE 999302) is a novel recombinant hCG purified from the human PER.C6®cell line. A recent placebo-controlled trial in women undergoing ovarian stimulation with follitropin delta demonstrated that the addition of 1 to 12 µg CG beta reduced the number of intermediate follicles and related hormones. This observation required further preclinical research to (1) evaluate whether the pharmacology of CG beta at LH/CGR was different than other hCG forms used in the clinic and/or (2) assess the effect of high concentrations of hCG and different hCG/FSH ratios on multiple follicular development and follicle atresia. Study design, size, duration Signaling properties of CG beta and other LH/hCG forms were compared at downstream pathways of LH/CGR in recombinant systems and human granulosa cells. To evaluate the effects of FSH±hCG in vivo, juvenile female rats were injected subcutaneously twice daily with follitropin delta ± CG beta/alfa for three days followed by an ovulatory dose of hCG. Oviducts were then collected for oocyte enumeration, ovaries and uteri were weighed, and ovaries were fixed for histological analysis. Participants/materials, setting, methods The pharmacology of CG beta and other LH/hCG forms was evaluated in a cAMP assay in human granulosa cells from follicular fluid from IVF patients and in recombinant systems, at the Gs, Gq and arrestin pathways. In the rat model, a dose response of follitropin delta (Rekovelle) was first evaluated, followed by evaluation of the dose-dependent effects of CG beta (0.00117-2.4 µg/kg), or CG alfa (Ovidrel/Ovitrelle), in combination with 1, 3 or 10 µg/kg rFSH. Main results and the role of chance The in vitro pharmacology (potency and efficacy) of CG beta was similar to recombinant LH, urinary hCG and recombinant hCG (CG alfa) tested at all proximal pathways evaluated downstream of LH/CGR as well as in human granulosa cells. In vivo, treatment with follitropin delta induced a bell-shaped dose-response curve for oocyte release with a maximum response of 40-50 oocytes at 8-10 µg/kg follitropin delta dose. The addition of CG beta dose-dependently potentiated the effects at low-to-mid follitropin delta doses but had inhibitory effects on the number of ovulated oocytes at high CG beta concentrations. The lowest CG beta dose that clearly reduced the number of ovulated oocytes was 2.4, 0.6 and 0.3 µg/kg in combination with a fixed dose of 1, 3 and 10 µg/kg follitropin delta, respectively, which indicated that the optimal hCG/FSH ratio and corresponding hCG efficacious dose was inversely related to the FSH dose. There was no difference between CG beta and CG alfa for the dose effect on the number of ovulated oocytes or ovarian weight. Histology data indicated many cystic follicles following high CG beta exposure which may represent atretic follicles prior to triggering follicular maturation and ovulation. Limitations, reasons for caution This is the first study demonstrating that the FSH dose in combination with the hCG dose determines the effect on multiple follicle growth, ovulation, and atresia. These observations need to be confirmed in clinical research, as doses and ratios applied in the rat cannot be extrapolated to the clinical setting. Wider implications of the findings A better understanding of the effect of different FSH to hCG ratios will help to improve current mixed protocols and design future recombinant combination products providing the optimal treatment outcome for each individual patient. Trial registration number not applicable

O-279 The type of gonadotrophin: Does it improve ART outcome?

Abstract Ovarian stimulation is a vital clinical component of an IVF cycle, with gonadotrophins being the main stimulation drugs. Follicle stimulating hormone (FSH), the key driver of follicle recruitment during an ovarian cycle is a complex glycosylated protein comprised of an α and β subunit with four glycosylation sites. Differences in glycosylation lead to heterogeneity with the FSH isoforms varying in their receptor binding and biological activity. The cyclic physiological variation of FSH isoforms and the FSH threshold/ window concept lead to the selection of a single dominant follicle during a menstrual cycle. Surpassing the FSH threshold and extension of the FSH window with ovarian stimulation using gonadotrophins salvages follicles with higher FSH sensitivity leading to multi-follicular development and retrieval of multiple oocytes. The first IVF birth in 1978 was from a natural cycle and was preceded by several unsuccessful attempts at oocyte retrieval. Ovarian stimulation was therefore incorporated into IVF treatment to overcome the inefficiencies encountered with a natural cycle. The objective of ovarian stimulation during IVF treatment is to obtain several mature oocytes, leading to good quality embryos for immediate replacement and cryopreservation for future use. An ideal stimulation wherein gonadotrophins are the mainstay is one that achieves maximal efficacy, safety and cost-effectiveness. Several gonadotrophin preparations have been available for clinical use over the years since the first use of pregnant mare serum gonadotrophin (PMSG) in 1940 and the first successful birth using human pituitary gonadotrophin (hPG) in 1961. These initial preparations were soon abandoned due to concerns with antigenicity and safety. Subsequent important milestones in the development gonadotrophins for clinical use include the urinary derived products, recombinant FSH preparations, long acting FSH and the biosimilars. Given the selection of gonadotrophins currently available, the apparent question is if they differ? Circulating FSH isoforms change during different stages of the menstrual cycle and through the reproductive stages. More acidic isoforms are predominant during the early follicular phase, with less acidic or basic isoforms predominant in the late follicular phase of the menstrual cycle, and more acidic isoforms during the menopausal stage. Similarly, the different FSH products vary in their properties owing to differences in their production and purification. Urinary derived products are more acidic compared to recombinant preparations and the different recombinant products vary in degree of acidity due to differences in the extent and pattern of glycosylation. The acidic and basic properties of gonadotrophin types influence metabolic stability, half-life and their biological activity. The question then remains if these differences in bioactivity affect clinical outcomes? Clinical effectiveness of the various gonadotrophins types should be addressed in the context of the different pituitary suppression regimens, ovarian response categories and patient variables given the implementation of individualised stimulation protocols. It is also imperative to clearly define successful clinical outcomes incorporating both efficacy and safety. Cumulative live birth rate (CLBR) following fresh and frozen embryo transfers resulting from one episode of ovarian stimulation should be adopted as the measure of the overall efficiency along with OHSS as a measure of immediate safety. There are several studies and systematic reviews comparing the different gonadotrophin types and products for various outcomes including surrogate endpoints, with inconsistent results attributed to differences in the inclusion/ exclusion criteria, heterogeneity across studies and varied quality of the primary studies. Furthermore, there have been sparse studies reporting on CLBR and there is a continuing debate on what would be considered as a relevant clinical difference in efficacy. In addition to efficacy and safety, the ultimate choice of gonadotrophin should be based on regional availability, patient acceptability and cost-effectiveness for a live birth.

Infertility Riding on Polycystic Ovarian Syndrome (PCOS): A Review of Treatment Modalities

Polycystic ovarian syndrome (PCOS) is the commonest cause of anovulatory infertility. Depending on the population studied between 5 and 18% of women of reproductive age suffer from PCOS, however not all of them are anovulatory or experience subfertility. PCOS has been associated with numerous reproductive and metabolic abnormalities. Despite enormous advances in the management of reproductive dysfunction, insight into the metabolic implications of PCOS is limited by the lack of uniform diagnostic criteria, the heterogeneity of the condition and the presence of confounders including obesity. Obesity clearly has a role in long term health and may best predict both reproductive and metabolic dysfunction as well as negatively affect the response to treatment in women with PCOS. Diabetes, cardiovascular disease and cancer are also at the forefront of any risk assessment or comprehensive treatment strategy for these women. Lifestyle modifications including dietary changes, increased exercise and weight loss are appropriate first line interventions for many women with PCOS. Pharmaceuticals including metformin, lipid lowering agents and oral contraceptives should be tailored to the individual’s risk profile and treatment goals. The fertility treatment in women with subfertility and PCOS aimed to safely induce monofollicular ovulation resulting in the birth of a singleton child. Women with PCOS undergoing fertility treatment are at risk of multi-follicular development as well as ovarian hyper-stimulation syndrome (OHSS), so they must be carefully counselled and monitored during fertility treatment. It is imperative that prior to embarking on fertility treatment, a patient’s health and weight is optimised. This chapter will explore the latest evidence for fertility treatments for women with PCOS.

A study of comparison of effectiveness of letrozole (5mg) versus clomephene citrate (100 mg) for ovulation induction among infertile women

Clomiphene citrate has been traditionally used as the drug of the choice for treatment of women with anovulatory infertility. In the last decade, an aromatase inhibitor, letrozole has emerged as an alternative ovulation induction agent among anovulatory women with polycystic ovarian syndrome. Letrozole has a definitive role in anovulatory women who have not responded to the clomiphene citrate therapy is confirmed by literatures. Anovulatory dysfunction is a common problem and is responsible for about 40% of female infertility and among causes; PCOS (polycystic ovarian syndrome) is the leading cause. Clomiphene citrate is considered as the drug of choice for the first line treatment of anovulatory dysfunction for a variety of reasons. Clomiphene citrate has some side effects like multi-follicular development and cyst formation and resistance of clomiphene are areas of concern and desire for an effective alternative persists.An aromatase inhibitor, letrozole, was introduced into infertility practice in the year 2000 and is regarded as a second line option, particularly in women with clomiphene resistance, and it has found acceptance in various clinical situations and the indications for use have expanded., To compare the efficacy of letrozole and clomiphene citrate (CC) for ovulation induction in infertile women. The study included 100 women presented with anovulatory infertility. The infertile women were divided into 2 groups of 50: Group A received 100 mg Clomiphene Citrate from day 3 to day 5 of menstruation and Estradiol Valerate 4 mg on the 12 day of menstruation until 16 day of menstruation; Group B treated by 5 mg Letrozole from day 3 to day 5 of the menstruation and as Group A, Estradiol Valerate 4 mg on the 12 day of menstruation until 16 day of menstruation given to Group B, with visits to determine ovulation and pregnancy, followed by tracking of pregnancies. Participants were of 20 to 39 years age, had normal uterine cavity and had a male partner with a sperm concentration of at least 14 million per millilitre; and during the study the women and their partners agreed to have regular intercourse with the intent of conception. The live birth during the treatment period was the primary outcome. Women who received letrozole had more cumulative live births than those women who had received clomiphene citrate (36 out of 50 [72%] vs. 28 out of 50 [56%]), without significant differences in overall congenital anomalies, there were no congenital anomalies. With letrozole as compared to clomiphene the cumulative ovulation rate was higher. Higher incidence of hot flushes was associated with a clomiphene, and letrozole was associated with fatigue and dizziness. Rates of other adverse effects were almost similar among these 2 groups. A significant difference in the follicular and endometrial development was evident among these 2 groups. As compared to with clomiphene, an aromatase inhibitor, letrozole was associated with higher live-birth and ovulation rates among infertile women. The results of the study demonstrated letrozole to be superior to clomiphene citrate in the maintenance of endometrial thickness.

P–661 Comparative assessment of the structural features of human follicle-stimulating hormone in products from multiple markets

Abstract Study question The aim of the study is to explore the structural differences occurring in recombinant human follicle-stimulating hormone alfa (r-hFSH- α), originator and its biosimilars, from various countries. Summary answer When compared with r-hFSH-α originator (Gonal-f), its biosimilars presented structural differences, namely Primapur showed a significant different glycosylation profile. What is known already FSH is part of cystine knot growth factor superfamily and plays a central role in reproduction, as FSH stimulates follicular development and estrogen synthesis. R-hFSH- α is commonly used in assisted reproductive technologies to achieve multifollicular development. At the present r-hFSH- α biosimilars are available in Europe and other regions. R-hFSH-α is a complex glycoprotein, that possesses several structural features critical for its efficacy and safety1–2. Glycosylation profile is one of the most impactful attributes of the molecule defining a moiety of FSH isoforms with impact on its biological net effect3. Efficacy and safety of r-hFSH- α are strictly correlated with glycoforms’ composition3–8. Study design, size, duration At least two different batches of each r-hFSH- α originator and its biosimilars have been included in the study. Participants/materials, setting, methods The structural features of products from six different marketed r-hFSH α (Gonal-f, Primapur, Folisurge Intas, Corneumon, Jin Sai Heng, Follitrope LG) have been investigated with a variety of analytical techniques in order to evaluate the presence of molecular differences, which could have a severe impact on the efficacy and safety of the product. The attributes which have been investigated in-depth include primary, secondary and tertiary structure as well as post-translational modifications (PTMs), including glycosylation and contaminants. Main results and the role of chance All r-hFSH- α biosimilars analyzed presented differences compared to the originator. We firstly investigated Primapur and found significant differences regarding multiple structural attributes, particularly in the glycosylation profile. Gonal-f exhibited lower glycan branching, expressed by an A-index* of 2.5, while Primapur showed an A-index of 2.4. Furthermore, Primapur showed a lower level of sialylation in comparison with Gonal-f, as measured by their respective S-index* of 1.8 and 2.1. FSH glycosylation exhibits both macroheterogeneity and microheterogeneity, impacting both FSH protein’s half-life and affinity with the follicle-stimulating hormone receptor (FSHR). Antennarity, representing FSH microheterogeneity, influence r-hFSH-α activity since it has been shown that bulky and extended glycans may take longer to fit into the FSHR cavity compared to less sterically hindering glycans, resulting in a delayed response 7,8.Additionaly, sialylation has been shown in-vivo to correlate with plasma half-life and effect on granulosa cells proliferation 1,2,3. The slower clearance of highly sialylated r-hFSH has been shown to lead to a higher in-vivo activity, despite the lower in-vitro bioactivity 1,2,3. *A-index and S-index express respectively a measure of the number of antennae and sialic acid per glycan. Final values are generated from many relative abundances normalized to 100, highlighting the significance of small numerical differences. Limitations, reasons for caution More batches should be tested for each product. The authors are presenting full characterization of only one of the biosimilars since the rest of the products are under characterization. Wider implications of the findings: r-hFSH-α originator and its biosimilar showed differences in terms of glycosylation profile that is well known as the major protein characteristic impacting FSH activity as extensively demonstrated in in-vivo and in-vitro models. This structural difference could have impact also on product efficacy and safety. Trial registration number ‘not applicable’

CLINICAL ANALYSIS OF CLOMIPHENE CITRATE INDUCED OVULATION IN INFERTILITY PATIENTS WITH POLYCYSTIC OVARIAN DISEASE

Background: Normo-gonadotrophic anovulation is the most prevalent anovulatory infertility type. Polycystic ovary disease (PCOS) is by far the most common cause in this category, accounting for 85 % of females who are anovulatory. Its prevalence is growing increasingly with increasing modernisation. Ovulation induction in PCOS females is a problem and the best drug for ovulation induction is still debatable. Aims &amp; objectives: In the current research, we evaluated the efficacy of clomiphene citrate in infertile women with polycystic ovary disease for ovulation induction and pregnancy rates. Material and Methods: The present research was a prospective study conducted with PCOS, willing to participate and follow up in women with primary/secondary infertility. Rotterdam criteria were used to diagnose PCOS. Using descriptive statistics, statistical analysis was performed. Results: Initially, 140 patients in the current study were recruited. For the current research, 128 patients either born or cared for a full 6 months were considered. 21-25 years of age was the most common age group. The mean age of the patients examined was 26.34 ± 3.6 years. 55 % were having average BMI patients, while 34% were overweight. Primary infertility was present in 77 percent of patients. 73 per cent of patients had infertility duration of 1-5 years. 30 percent have a history of laparoscopic ovarian drilling in patients. In 58 percent, hirsutism was noted. Following serial USG monitoring, mono-follicular development (55 %) was more prevalent than multi-follicular development at the end of the study (45 percent). The mean thickness of the endometrium was 7.78 ± 2.58 mm. The mean days for clomiphene citrate ovulation are 14.84 ± 3.46. Average P4 values on day 21 were 11.48 ± 6.44 ng/ml. At the end of the study, 66 % ovulation rate, 28 % pregnancy rate, and 2 % multiple pregnancy incidence were noted. Conclusion: Ovulation induction with clomiphene citrate should be considered as the first line of treatment for infertile women with PCOS. Initial assessment and careful selection of patients increases pregnancy rates. Keywords: ovulation induction, polycystic ovary disease, clomiphene citrate, pregnancy rate.

The Effect of Serum Estradiol Level at the Time of HCG Injection on the ICSE Outcome

Background: In addition to multi-follicular development, controlled stimulation of ovaries is associatedwith a high serum level of estradiol (E2). The increased serum E2 level during COS may therefore beassociated either with an increased chance of pregnancy or an impaired reproductive outcome secondary tochanged endometrial receptivity.Objective: To assess the effect of serum estradiol level at the day of hCG administration on the success ofintracytoplasmic sperm injection (ICSI) cyclesPatients and Method: A retrospective study, in which a total of 235 women who were undergo a singleICSI cycle were introduced in this retrospective study, All patients were received gonadotrophin agonisteither short or long protocol. The patients were classified at the day of hCG administration into three groupsaccording to serum E2 level group A &lt;1000pg/ml, group B 1000-3000pg/ml and group C &gt;3000pg/ml.Results: The mean number of retrieved oocytes and embryos obtained in group C were more than in groupA and B but clinical pregnancy rate was higher in group B than in group A and group C which is statisticallysignificant.Conclusion: Although there is no high quality evidence to support a positive correlation between serum E2levels and IVF-ICSI products, the E2 level in the serum may has a level –dependent effect on the successof pregnancy. The optimal range of serum E2 is 1000-3000pg/ml is associated with higher rate of clinicalpregnancy

COST EFFECTIVE PROTOCOL WITH LETROZOLE AND 3 DOSES OF GONADOTROPIN COMBINATION AS AN ALTERNATIVE TO CONTINUOUS GONADOTROPIN FOR OVULATION INDUCTION FOR IUI IN CLOMIPHENE CITRATE RESISTANT PCOS PATIENTS - A RCT

Clomiphene citrate (CC) is the primary drug of choice for ovulation induction in PCOS but resistance to ovarian stimulation or stunted follicular growth is a frequent observation with CC. Inappropriate pregnancy rate & inadequate pregnancy outcomes are also observed with CC. The next approach of ovulation induction in CC resistance cases is using continuous Gonadotropin but it has many disadvantages such as high treatment cost, multi follicular development leading to multiple pregnancy, OHSS and frequent shifting of cycle to IVF-ET treatment. Letrozole induces folliculogenesis by releasing H-P axis from tonic inhibitory effect of estrogen & by augmenting gonadotropin secretion. It helps in follicular development without any adverse effect on the peripheral estrogen sensitive tissues. Adding few ampoules of gonadotropin at interval along with letrozole increases FSH at follicular receptor level & produces good quality oocyte. The purpose of the study was: -To evaluate the efficacy of combined Letrozole & 3 doses of gonadotropin in CC resistant IUI cases. -To compare the efficacy and cost effectivity of this protocol with continuous gonadotropin therapy. This RCT was conducted in a tertiary infertility care centre from July 2017 to January 2019. Total 108 anovulatory PCO women in the age group 20 to 36 years who had previous ≥3 failed treatment cycles with CC were randomly divided into Group A (Letrozole plus 3 doses gonadotropin group) & Group B (Continuous gonadotropin group) comprising 54 patients in each group. 2 blood samples from all the patients on Day2 of cycle and on the Day of hCG triggering were analyzed for endocrine profile. Patients in gr A were studied for total 96 cycles (n = 96) who received tab Letrozole 5 mg daily from D2 to D6 and injection U-FSH- HP (75 IU) on D2, D5 and D8 of cycle. Patients in gr B were studied for total 84 cycles (n = 84) & received continuous gonadotropin (U-FSH- HP, 75 IU) starting from D2 of cycle. Folliculometry was started from D9 of cycle & ovulation triggering was done by hCG when dominant follicle reached ≥ 18 mm. Single IUI was performed with documented ovulation. Both groups were evaluated in respect of terminal endocrinological profile, number of follicles, ovulation rate, pregnancy rate & outcome, adverse effects & cost effectivity. Demographic & baseline endocrine profile was comparable. In Gr A & B, mean no of follicles and average terminal estradiol level were 1.8 ±0.6 Vs 4.2 ± 0.8 (p< 0.05) and 266 ± 46 Vs 756 ± 84 pg (p< 0.001) respectively. Ovulation rate and pregnancy rate in both groups were 83.3% Vs 90.5% (p = 0.157) and 18.8% Vs 20.2% (p = 0.774) in Gr A & B respectively. In Gr B, 3 patients (3.6%) developed OHSS and 4 patients (4.8%) needed shifting of cycle to IVF-ET whereas no such incidents happened in Gr A. The average cost per cycle was significantly less in Gr A than Gr B. The combined therapy with Letrozole and 3 doses of gonadotropin is a cost effective treatment protocol in CC resistant PCOS patient before proceeding to costly continuous gonadotropin therapy without any significant difference in ovulation and pregnancy rate.

LIVE BIRTH RATES AND OVARIAN HYPERSTIMULATION SYNDROME (OHSS) RISK WITH RECOMBINANT FOLLITROPIN ALFA BIOSIMILAR PREPARATIONS VERSUS ORIGINATOR PREPARATIONS: A SYSTEMATIC REVIEW AND META-ANALYSIS

Follitropin alfa is used for ovulation induction or stimulation of multifollicular development in women undergoing assisted reproductive technologies (ART). Published randomized controlled trials (RCTs) comparing originator follitropin alfa and biosimilar preparations were not powered to assess clinically relevant outcomes. We performed a systematic review and meta-analysis to compare clinically relevant outcomes between the originator and biosimilar preparations across head-to-head RCTs.

Does multifollicular development and number of intermediate follicles contribute to the effect of luteal phase support with vaginal progesterone gel in intrauterine insemination cycles?

Luteal phase deficiency as a result of multifollicular development which produces supraphysiological progesterone and estradiol levels and benefit of luteal phase support have been proven in assisted reproductive technique (ART) treatment. But, there were some controversial results in intrauterine insemination (IUI) cycles whether luteal phase support (LPS) with progesterone have an impact on pregnancy outcome. To assess the efficacy of vaginal progesterone gel in the gonadotropin-induced IUI cycles, this retrospective data analysis compared the luteal phase support and control group in terms of clinical pregnancy (CPR) and live birth rates (LBR). In subgroup analysis, multifollicular and monofollicular growth were analyzed separately. In total, after exclusion criteria, 380 IUI cycles were analyzed, cycles were grouped as LPS(+) and LPS(-) with 190 and 190 cycles, respectively. CPR and LBR were comparable between groups (11.6% vs. 10.5, p = .74 and 8.9% vs. 8.4%, p = .75 respectively). Although multifollicular growth demonstrated higher pregnancy outcomes than monofollicular growth, intermediate follicles (14–16 mm) had a positive impact on pregnancy outcome in monofollicular growth like multifollicular subgroup. We found no difference in CPR and LBR according to the luteal phase vaginal progesterone gel. Nevertheless, multifollicular cycles and also monofollicular growth cycles with two and more intermediate follicles may have benefit LPS in gonadotropin-induced IUI cycles.

Ultrasound monitoring during first-cycle treatment with clomifene citrate: a national survey of compliance with NICE

The National Institute for Health and Care Excellence Clinical Guideline 156 advises that transvaginal ultrasonography (TVUS) should be used in the first cycle of treatment with clomifene citrate, to assess for multifollicular development and hence the risk of multiple pregnancy. This guidance is based on expert opinion rather than research evidence. We conducted a cross-sectional online and postal survey among UK-based consultant gynaecologists and fertility specialists, to explore compliance with this guideline. A total of 110 responses met the inclusion criteria. During first-cycle treatment with clomifene, 50.9% of respondents were not always using TVUS, and 21.8% never were. Clinicians who did not have immediate access to TVUS were significantly less likely to scan (p < 0.01). Other key factors influencing practice were, personal experience of the clinician, lack of an evidence base to support the guideline and a willingness to accept the risk of multiple pregnancy. Several respondents questioned the value of scanning the first cycle only and highlighted that over-response may be seen in subsequent cycles. This study confirms that there is variation in adherence to the guideline and uncertainty about the clinical need for scan monitoring. Further evidence to support or refute the guideline is required.

Individualised gonadotropin dose selection using markers of ovarian reserve for women undergoing in vitro fertilisation plus intracytoplasmic sperm injection (IVF/ICSI).

Individualised gonadotropin dose selection using markers of ovarian reserve for women undergoing in vitro fertilisation plus intracytoplasmic sperm injection (IVF/ICSI).