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Reproductive medicine is actively developing, and new methods, drugs, and protocols are being developed and introduced for the treatment of infertility. Assisted reproductive technologies (ART) are the most effective methods. In ART protocols, ovarian stimulation (OS) is based on gonadotropin use. The choice of the starting dose of gonadotropin is a critical factor in the successful OS and the effectiveness of ART programs. The article describes the development history of gonadotropins and provides current data on their use in ART programs. The use of biosimilars of follitropin alfa in OS is discussed, and the effectiveness of its Russian biosimilar is also addressed. TRANSLATE with x English Arabic Hebrew Polish Bulgarian Hindi Portuguese Catalan Hmong Daw Romanian Chinese Simplified Hungarian Russian Chinese Traditional Indonesian Slovak Czech Italian Slovenian Danish Japanese Spanish Dutch Klingon Swedish English Korean Thai Estonian Latvian Turkish Finnish Lithuanian Ukrainian French Malay Urdu German Maltese Vietnamese Greek Norwegian Welsh Haitian Creole Persian TRANSLATE with COPY THE URL BELOW Back EMBED THE SNIPPET BELOW IN YOUR SITE Enable collaborative features and customize widget: Bing Webmaster Portal Back

Introduction. Approaches to treatment of infertility have been progressively updated because the field of assisted reproductive technologies (ART) is a science-based symbiosis of the latest knowledge and advances in medicine, biology, and genetics. Today, a real-world clinical practice of a reproductive specialist needs to be assessed in the Russian Federation (RF) both in terms of a retrospectively analyzed development of RF in vitro fertilization (IVF) technologies and identifying promising approaches for infertility treatment in the future.Aim: analysis of current therapeutic tendencies and promising trends in real clinical practice of infertility in the Russian Federation.Materials and Methods. In 2022–2023 under the auspices of the Institute for Preventive and Social Medicine and the National Alliance for Public Health Advancement, a survey of reproductive doctors practicing at commercial and government ART centers was carried out. The questionnaire contained questions regarding describing a RF female patient’s portrait with an expected ovarian reserve and response to ovarian stimulation to propose a choice of ovarian stimulation protocol as well as basic and concomitant pharmacotherapy.Results. The opinion of 425 fertility doctors from 156 ART centers in 42 cities of the Russian Federation was assessed. A portrait of a female patient with infertility in the Russian Federation was determined in accordance with the ovarian reserve, expected response to gonadotropin-based stimulation (normal response – 40 %, hyporesponse – 40 %, hyperresponse – 20 % of patients). The basic pharmacotherapy in the stimulation protocol in the IVF program based on agonists and antagonists of gonadotropinreleasing hormone (GnRH), various gonadotropin-containing drugs in female patients with expected normal, hypo- and hyperresponse to ovarian stimulation was assessed. The dominant protocol consists of using GnRH antagonist most often observed in patients with hyper- (95 % of cases), normal (75 % of cases) and hypo-response (45.5 %). Preferences in the basic and concomitant pharmacotherapy in IVF programs were identified as well as current trends in embryo transfer in fresh and cryoprotocols (a tendency to freeze all obtained embryos - “freeze-all” strategy), preimplantation genetic testing methods (used in 30 % of protocols in normal responders, 60 % in hyporesponders and 10 % in hyperresponders) were described.Conclusion. Our study provides the most large-scale analysis of the real-world clinical practice of RF reproductive specialists. A portrait of a RF female patient with infertility, expected ovarian reserve and response to ovarian stimulation was described. Contemporary approaches to select stimulation protocol, basic and concomitant pharmacotherapy in real-world clinical practice were identified. The data obtained represent an important significant cross-section for current practical approaches in real-world practice of RF fertility doctors and can serve as the basis for assessing developing ART methods in the Russian Federation as well as be used to create an evidence base for analyzing future clinical and economic effectiveness of IVF programs in the Russian Federation.

The gonadotropins (Gth), follicle-stimulating hormone (Fsh) and luteinizing hormone (Lh), play central roles in gametogenesis in vertebrates. However, available information on their differential actions in teleost, especially in vivo, is insufficient. In this study, we established stable CHO-DG44 cell lines expressing long-lasting recombinant Japanese eel Fsh and Lh with extra O-glycosylation sites (Fsh-hCTP and Lh-hCTP), which were produced in abundance. Immature female eels received weekly intraperitoneal injections of Gths. Fsh-hCTP induced the entire ovarian development by 8 weeks from the beginning of injection; thus, the ovaries of most fish were at the migratory nucleus stage while the same stage was observed in eels after 4 weeks in the Lh-hCTP-treated group. In contrast, all pretreated and saline-injected eels were in the pre-vitellogenic stage. Gonadosomatic indices in the Fsh-hCTP-treated group were significantly higher than those in the Lh-hCTP group at the migratory nucleus stage because of the significantly higher frequency of advanced ovarian follicles. Ovarian mRNA levels of genes related to E2 production (cyp11a1, cyp17a1, cyp19a1, hsd3b, fshr, and lhr) were measured using real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR). All genes were induced by both Fsh-hCTP and Lh-hCTP, with a peak at either the mid- or late vitellogenic stages. Transcript abundance of cyp19a1 and fshr in the Lh-hCTP group were significantly higher than those in the Fsh-hCTP group, whereas no difference in the expression of other genes was observed between the groups. Fluctuations in serum levels of sex steroid hormones (estradiol-17β, 11-ketotestosterone, and testosterone) in female eels were comparable in the Fsh-hCTP and Lh-hCTP groups, thus increasing toward the maturational phase. Furthermore, the fecundity of the eels induced to mature by Fsh-hCTP was significantly higher than that induced by Lh-hCTP. These findings indicate that Fsh and Lh can induce ovarian development in distinctively different modes in the Japanese eel.

Background: Treatment with recombinant gonadotropin hormones (rGths), follicle-stimulating hormone (rFsh) and luteinizing hormone (rLh), was shown to induce and complete vitellogenesis to finally obtain viable eggs and larvae in the flathead grey mullet (Mugil cephalus), a teleost arrested at early stages of gametogenesis in intensive captivity conditions. This study aimed to investigate the transcriptomic changes that occur in the ovary of females during the rGths-induced vitellogenesis. Methods: Ovarian samples were collected through biopsies from the same five females at four stages of ovarian development. RNASeq libraries were constructed for all stages studied, sequenced on an Illumina HiSeq4000, and a de novo transcriptome was constructed. Differentially expressed genes (DEGs) were identified between stages and the functional properties of DEGs were characterized by comparison with the gene ontology and Kyoto Encyclopedia. An enrichment analysis of molecular pathways was performed. Results: The de novo transcriptome comprised 287,089 transcripts after filtering. As vitellogenesis progressed, more genes were significantly upregulated than downregulated. The rFsh application induced ovarian development from previtellogenesis to early-to-mid-vitellogenesis with associated pathways enriched from upregulated DEGs related to ovarian steroidogenesis and reproductive development, cholesterol metabolism, ovarian growth and differentiation, lipid accumulation, and cell-to-cell adhesion pathways. The application of rFsh and rLh at early-to-midvitellogenesis induced the growth of oocytes to late-vitellogenesis and, with it, the enrichment of pathways from upregulated DEGs related to the production of energy, such as the lysosomes activity. The application of rLh at late-vitellogenesis induced the completion of vitellogenesis with the enrichment of pathways linked with the switch from vitellogenesis to oocyte maturation.Conclusion: The DEGs and enriched molecular pathways described during the induced vitellogenesis of flathead grey mullet with rGths were typical of natural oogenesis reported for other fish species. Present results add new knowledge to the rGths action to further raise the possibility of using rGths in species that present similar reproductive disorders in aquaculture, the aquarium industry as well as the conservation of endangered species. [ABSTRACT FROM AUTHOR]

Background: Treatment with recombinant gonadotropin hormones (rGths), follicle-stimulating hormone (rFsh) and luteinizing hormone (rLh), was shown to induce and complete vitellogenesis to finally obtain viable eggs and larvae in the flathead grey mullet (Mugil cephalus), a teleost arrested at early stages of gametogenesis in intensive captivity conditions. This study aimed to investigate the transcriptomic changes that occur in the ovary of females during the rGths-induced vitellogenesis.Methods: Ovarian samples were collected through biopsies from the same five females at four stages of ovarian development. RNASeq libraries were constructed for all stages studied, sequenced on an Illumina HiSeq4000, and a de novo transcriptome was constructed. Differentially expressed genes (DEGs) were identified between stages and the functional properties of DEGs were characterized by comparison with the gene ontology and Kyoto Encyclopedia. An enrichment analysis of molecular pathways was performed.Results: The de novo transcriptome comprised 287,089 transcripts after filtering. As vitellogenesis progressed, more genes were significantly upregulated than downregulated. The rFsh application induced ovarian development from previtellogenesis to early-to-mid-vitellogenesis with associated pathways enriched from upregulated DEGs related to ovarian steroidogenesis and reproductive development, cholesterol metabolism, ovarian growth and differentiation, lipid accumulation, and cell-to-cell adhesion pathways. The application of rFsh and rLh at early-to-mid-vitellogenesis induced the growth of oocytes to late-vitellogenesis and, with it, the enrichment of pathways from upregulated DEGs related to the production of energy, such as the lysosomes activity. The application of rLh at late-vitellogenesis induced the completion of vitellogenesis with the enrichment of pathways linked with the switch from vitellogenesis to oocyte maturation.Conclusion: The DEGs and enriched molecular pathways described during the induced vitellogenesis of flathead grey mullet with rGths were typical of natural oogenesis reported for other fish species. Present results add new knowledge to the rGths action to further raise the possibility of using rGths in species that present similar reproductive disorders in aquaculture, the aquarium industry as well as the conservation of endangered species.

Introduction. The efficacy and safety of biosimilar follitropin alpha have been demonstrated in randomized blinded prospective clinical trials of phases I and III. Unfortunately, there is a gap between the clinical trials and real clinical practice data. The real-world patient data helps to create an evidence-based background for successful implementation of medicine at everyday practice in a nonselected population.Aim: to investigate the efficacy of follitropin alpha biosimilar therapy (Primapur®) in nonselected real-world population.Materials and Methods. A retrospective observational anonymized cohort study of follitropin alpha biosimilar (Primapur®) as a pre-filled pen injector with a dose adjustment of 5 IU, aimed to investigate its efficacy and safety in a nonselected population with indications to assisted reproductive technologies (ART) was carried out. The ovarian stimulation (OS) protocols included: monotherapy protocols with using only Primapur®; mixed protocols (recombinant and urinary-derived gonadotropins); short protocols with using antagonists of gonadotropin-releasing hormone (GnRH) and long protocols with GnRH agonists. The stimulation protocols were analyzed with Primapur® application for at least 5 days.Results. The overall clinical efficacy of ovarian stimulation cycles (N = 5484) was: oocytes retrieved - 9.5 ± 7.2, mature (MII) - 6.8 ± 6.6, fertilized (2PN) - 6.1 ± 5.8, clinical pregnancy per ET (PR) - 38.4 %. Mixed gonadotropin protocols (N = 2625) vs. monotherapy with Primapur® (N = 2859): oocytes retrieved - 8.6 ± 6.8 vs. 10.3 ± 7.4 (p < 0.001), mature (MII) - 6.7 ± 6.2 vs. 7.7 ± 6.9 (p < 0.001), fertilized (2PN) - 5.8 ± 5.2 vs. 7.2 ± 6.2 (p < 0.001). There were statistically significant differences between oocyte yields in mixed vs. monotherapy protocols due to subgroup differences, including age, body mass index (BMI) and IVF/ICSI attempts. No statistically significant differences were found for PR: 39.3 % vs. 37.6 % (p = 0.314). Monotherapy protocols with GnRH antagonist OS (N = 2183) vs. GnRH agonist (N = 676) revealed: oocytes retrieved - 10.5 ± 7.5 vs. 9.6 ± 7.0 (p = 0.032), mature (MII) - 7.6 ± 6.9 vs. 6.7 ± 5.7 (p < 0.001), fertilized (2PN) - 7.3 ± 6.3 vs. 5.7 ± 5.0 (p < 0.001). There were statistically significant differences between BMI and IVF/ICSI attempts. No statistically significant differences were found for PR: 37.9 % vs. 35.9 % (p = 0.482). All medicines were well tolerated and no serious adverse reactions were reported.Conclusion. This was the largest retrospective observational study conducted in the field of fertility in Russia and involved 5484 ovarian stimulation protocols at 35 IVF clinics. The obtained results demonstrated similar clinical efficacy for follitropin alpha biosimilar Primapur® in different OS protocols in real clinical practice.

Background: It is debated whether the use of recombinant follicle-stimulating hormone (r-FSH) or human menopausal gonadotropin (HMG) is associated with progesterone (P) elevation in the late follicular phase. Aims: The aim is to determine whether the type of gonadotropin used for controlled ovarian stimulation (COS) in in vitro fertilization (IVF) is associated with P elevation in the late follicular phase using antagonist protocol. Setting and Design: This was a retrospective data analysis in the IVF unit. Methods: Data of women who underwent COS between January 2005 and December 2017. Statistical Analysis: Chi-square and unpaired Student's t-test in SPSS 20. Results: Data of 439 women was analyzed. Mean age was 31.45 ± 4.6 years. HMG was used in 193 (44%), r-FSH in 232 (52.8%), and a combination of both in 14 (3.2%) women. Proportion of women with elevated P was significantly higher in r-FSH group as compared to HMG group (19/232 [8.2%] vs. 6/193 [3.1%]; P= 0.027). Mean P levels were significantly higher in r-FSH group (0.75 ng/ml vs. 0.59 ng/ml; P = 0.049). Mean estradiol (E2) levels at trigger were significantly higher in women with elevated P as compared to normal P(2893.4 ± 2091.8 pg/ml vs. 1668.3 ± 1508.6 pg/ml respectively; P< 0.000). Fresh embryo transfers performed in 18/27 women with elevated P resulted in pregnancy in three (16.7%) women. Two had biochemical pregnancies and one was lost to follow-up. Conclusions: Use of r-FSH and E2 levels at trigger are associated with elevated P levels in the late follicular phase. Fresh embryo transfers performed in spite of elevated P levels were associated with low pregnancy rates and unfavorable outcomes.

ABSTRACT: Background: Poor ovarian responders generally refer to patients who respond poorly to ovarian stimulation for assisted reproductive techniques (ART) such as in-vitro fertilization (IVF) and hence experience low live birth rate. Various controlled ovarian stimulation (COS) protocols have been developed during the past 3 decades for IVF/ICSI to improve oocyte quality and ultimately live birth rate, to increase ovarian response in POR patients, and to reduce the risk of ovarian hyperstimulation syndrome. Both highly puri?ed human menopausal gonadotropin (hp-hMG) and recombinant follicle-stimulating hormone (rFSH) have been widely used for COS during IVF/ICSI. Their in?uence on treatment outcome in women undergoing IVF/ICSI hasbeen actively debated. Objectives: To compare highly purified human menopausal gonadotropin (hp-hMG) and recombinant follicle-stimulating hormone (rFSH) in patients with poor ovarian response undergoing in vitro fertilization/intracytoplasmic sperm injection with a gonadotropin-releasing hormone antagonist protocol. Methods: This retrospective cohort study included 60 patients with poor ovarian response (30 received hp-hMG and 30 received rFSH) undergoing in vitro fertilization/intracytoplasmic sperm injection with a gonadotropin-releasing hormone antagonist protocol. Pregnancy-related outcomes, ovarian response, oocyte, and embryo parameters were compared between the 2 groups. Additionally, serum insulin-like growth factor-1 and insulin-like growth factor binding protein-1 levels on the day of oocyte retrieval were compared between the 2 groups. Results: The 2 treatments resulted in comparable numbers of oocytes retrieved and embryos, comparable oocyte retrieval rate, mature oocyte rate, and fertilization rate, and also comparable clinical pregnancy rates, implantation rates, and miscarriage rate. However, hp-hMG led to statistically insignificant higher viable embryo rate (54.0% vs 44.8%; P = 0.174) and live birth rate per pregnancy (16.7% vs 10%) versus rFSH. Finally, statistically significantly higher serum insulin-like growth factor-1 level (178.53 [13.70] ng/mL vs 164.93 [12.17] ng/mL; P = 0.01) and statistically insignificantly lower serum insulin-like growth factor binding protein-1 level (19.53 [3.56] ng/mL vs the lower insulin-like growth factor binding protein-1 level SD is (2.76 [20.83] ng/mL; P > 0.05) on the day of oocyte retrieval were associated with hp-hMG versus rFSH. Conclusions: hp-HMG and rFSH did not lead to significantly different treatment outcomes in patients with poor ovarian response undergoing in vitro fertilization/intracytoplasmic sperm injection with a gonadotropin-releasing hormone antagonist protocol, although significantly higher serum insulin-like growth factor-1 level and insignificantly lower serum insulin-like growth factor binding protein-1 level on the day of oocyte retrieval associated with hp-HMG might suggest a beneficial endocrine environment. (Curr Ther Res Clin Exp. 2020; 81:XXX–XXX)

A clinical study on the efficacy and safety of follitropin alfa has been conducted. The aim of the study was to confirm the therapeutic equivalence between the follitropin alfa biosimilar (Primapur®) and the reference medication (Gonal-f®) in controlled induction of superovulation within the assisted reproductive technologies (ART) programs. Materials and methods. This multicenter, randomized, blind at the embryological stage, in parallel groups, comparative study of phase III (RCT 754 from 26.10.16/NCT03088137) involved 110 women aged 20-35 years with established causes of infertility (tubal factor, male factor). The patients were randomized into 2 equal groups of 55 participants each. The primary end-point for assessing the therapeutic equivalence was the number of aspirated oocytes. The secondary end-points included the number of fertilized oocytes, the number of days of stimulation, the total dose of the injected drug, the occurrence rate of biochemical and clinical pregnancies. Results. In this study, the follitropin alfa biosimilar was shown to be equivalent to the original follitropin in terms of the number of aspirated oocytes. Also, no statistically significant differences were found in the number of mature and fertilized oocytes, the days of stimulation, the dose of the drug administered during the treatment, and the rate of the onset of biochemical or clinical pregnancy. Conclusion. The therapeutic equivalence between the follitropin alfa containing Primapur® and Gonal-f® has been demonstrated.

To date, self administrations of recombinant human follicle-stimulating hormone (rhFSH) are carried out using pen injectors with minimal dose increments of 8.33 IU or 12.5 IU (IU – international units of activity). To ensure the accuracy of dose titration and to minimize the dose adjustments during the treatment, new pen injectors are needed. Those would provide for the self administration of rhFSH in a wide range of doses and with a dose increment less than the existing fractional values. Aim: to develop a pre-filled, multi-dose pen injector for rhFSH solution with a 5 IU dose increment and a dose setting from 0 to 300 IU.Materials and methods. Dispensed volumes containing the minimal dose of 5 IU were measured gravimetrically.Results. After testing 48 pen injectors the estimated minimal dose of 5 IU (0.0083 ml of the solution) produced the following results: the mean value of the dispensed volume was 0.0081 ml, the mean deviation was ± 0.0006 ml (or ± 0.36 IU). The results are in consistence with the ISO 11608-1:2014(E) requirements of dose accuracy for the minimal dose setting in commercial injectors.Conclusion. We have developed a pen injector for rhFSH administration with a dose setting from 0 to 300 IU and with a minimal increment of dose adjustment of 5 IU. The individual approach to the dose selection/adjustment with a minimal increment of 5 IU may help achieving a highly accurate administration of rhFSH for the controlled ovarian hyperstimulation and for the induced-ovulation protocols with growth activation of 1-2 follicles.

Within the framework of the 27th international conference «Reproductive technologies today and tomorrow», the first Russia-made follitropin alfa biosimilar for controlled ovarian stimulation in assisted reproductive technologies (ART) was presented. The follicle-stimulating hormone (FSH) biosimilar has undergone all stages of development in Russia, from the producer cells culture to the release of active FSH. Also the data are presented on a prospective randomized crossover study of phase I confirming the similarity of pharmacokinetics between the biosimilar and the original FSH. Another randomized multicenter phase III clinical study is now under way aiming to demonstrate the clinical equivalence between the biosimilar and the original FSH; preliminary results of this study are presented and discussed. As planned, the recombinant FSH biosimilar will be produced in disposable injectors (pen-injector) that provide easy-to-use handling, convenient dose setting and wide range dosing.

Objective: The aim of the present study was to investigate the therapeutic equivalence between the follitropin alpha biosimilar and the reference medication in women undergoing assisted reproductive technologies (ART).Study Design: This multicenter, randomized (1:1), embryologist-blinded, parallel-group, comparative phase III study involved 110 women aged 20-35 years old with tubal and/or male factors of infertility. All of the subjects underwent controlled ovarian hyperstimulation (COH) using a gonadotropin-releasing hormone antagonist (GnRH-ant) protocol. Over the 5-day fixed-dose regimen, the women received 150 IU/day of follitropin alpha biosimilar (n = 55) or original follitropin alpha (n = 55), followed by dose adaptation. The primary endpoint for assessing the therapeutic equivalence was the number of retrieved oocytes using a pre-determined clinical equivalence margin of ± 3.4 oocytes.Results: Similar numbers of oocytes were retrieved in both groups: 12.16 ± 7.28 in the follitropin alpha biosimilar group and 11.62 ± 6.29 in the original follitropin alpha group, with mean difference of 0.546 ± 1.297 oocytes (95% confidence interval [CI]: -2.026, 3.116), p = 0.002 (intention-to-treat [ITT] population). Additionally, no statistically significant differences were found for secondary endpoints: the onset of biochemical (34.7% and 36.7%, p = 0.883), clinical pregnancy (26.5% and 32.7%, p = 0.507), delivery (26.5% and 24.5%, p = 0.817) and take-home baby rate (28.6% and 26.5%, p = 0.816) for the follitropin biosimilar and original follitropin groups (per-protocol [PP] population). Ovarian hyperstimulation syndrome was observed in subjects with a positive pregnancy test in 0% and 3.64% of cases and after triggering ovulation in 7.27% and 3.64% for the follitropin biosimilar and original follitropin groups, respectively.Conclusions: This study demonstrated similar therapeutic equivalence and safety profiles between the follitropin alpha biosimilar and the reference follitropin in women who underwent COH in GnRH-ant cycles.Trial Registration Number: 1. Name of the registry: ClinicalTrials.gov.Trial Registration Number: NCT03088137. Date of registration: 02.03.2017, retrospectively registered. Trial conducted between 08.02.2017 and 17.08.2018, the date of enrollment of the first participant - 08.02.2017. 2. Name of the registry: Russian Ministry of Health, grls.rosminzdrav.ru.Trial Registration Number: RCT 754. Date of registration: 26.10.2016, prospectively registered. [ABSTRACT FROM AUTHOR]

Background: It is debated whether the use of recombinant follicle-stimulating hormone (r-FSH) or human menopausal gonadotropin (HMG) is associated with progesterone (P) elevation in the late follicular phase. Aims: The aim is to determine whether the type of gonadotropin used for controlled ovarian stimulation (COS) in in vitro fertilization (IVF) is associated with P elevation in the late follicular phase using antagonist protocol. Setting and Design: This was a retrospective data analysis in the IVF unit. Methods: Data of women who underwent COS between January 2005 and December 2017. Statistical Analysis: Chi-square and unpaired Student's t-test in SPSS 20. Results: Data of 439 women was analyzed. Mean age was 31.45 ± 4.6 years. HMG was used in 193 (44%), r-FSH in 232 (52.8%), and a combination of both in 14 (3.2%) women. Proportion of women with elevated P was significantly higher in r-FSH group as compared to HMG group (19/232 [8.2%] vs. 6/193 [3.1%]; P = 0.027). Mean P levels were significantly higher in r-FSH group (0.75 ng/ml vs. 0.59 ng/ml; P = 0.049). Mean estradiol (E2) levels at trigger were significantly higher in women with elevated P as compared to normal P (2893.4 ± 2091.8 pg/ml vs. 1668.3 ± 1508.6 pg/ml respectively; P < 0.000). Fresh embryo transfers performed in 18/27 women with elevated P resulted in pregnancy in three (16.7%) women. Two had biochemical pregnancies and one was lost to follow-up. Conclusions: Use of r-FSH and E2 levels at trigger are associated with elevated P levels in the late follicular phase. Fresh embryo transfers performed in spite of elevated P levels were associated with low pregnancy rates and unfavorable outcomes. [ABSTRACT FROM AUTHOR]

Objective: To compare the Follicular Output Rate (FORT) between corifollitropin alfa (CFA) and recombinant follicle-stimulating hormone (rFSH) during controlled ovarian stimulation (COS).Study Design: This retrospective analysis compared FORT between women treated with CFA or rFSH from three clinical trials: ENGAGE (N = 1476; ages 18-36, >60 kg), ENSURE (N = 395; ages 18-36, ≤60 kg), and PURSUE (N = 1388; ages 35-42, ≥50 kg). Women underwent COS in a GnRH antagonist protocol followed by hCG trigger prior to IVF. Antral follicle count (AFC; <11 mm) and pre-ovulatory follicle count (>15 mm) were used for FORT, defined as [pre-ovulatory follicles/AFCx100].Results: For CFA and rFSH, respectively, mean FORT (adjusted for trial and age) was 85.0 versus 76.8 (p < 0.001) in the combined cohort, 86.0 versus 75.0 in ENGAGE (p < 0.001), 96.2 versus 79.2 in ENSURE (p = 0.070), and 74.1 versus 71.2 in PURSUE (p = 0.180); mean oocyte output (oocytes retrieved/AFCx100, adjusted for age) was 121.9 versus 107.3 in ENGAGE (p = 0.001), 133.5 versus 102.3 in ENSURE (p < 0.001), and 100.6 versus 98.1 in PURSUE (p = 0.463). FORT and oocyte output were consistent with the number of metaphase II oocytes retrieved for CFA and rFSH: 10.4 versus 8.8 in ENGAGE (p < 0.001), 10.3 versus 7.6 in ENSURE (p < 0.001), and 7.5 versus 7.2 in PURSUE (p = 0.37). No differences in pregnancy rates based on FORT were observed.Conclusions: FORT was significantly higher in CFA-stimulated cycles and accurately predicted oocyte output. No association of FORT with pregnancy likelihood was found. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate whether oral myo-inositol supplementation (MI) is able to reduce the amount of gonadotropins (GA) and the length of controlled ovarian hyperstimulation (SL) in both Polycystic Ovarian Syndrome (PCOS) and non-PCOS women undergoing in vitro fertilization (IVF).Methods: We performed a systematic review (PROSPERO ID: CRD42017069439) of randomized controlled trials (RCTs). We searched articles published in English between January 1985 to August 2017, using the combination of the Medical Subject Headings "Inositol" with "Ovulation Induction", "follicle-stimulating hormone, human, with HCG C-terminal peptide", "Reproductive Techniques, Assisted", and "Fertilization in Vitro". We collected data about GA and SL comparing MI to no treatment or D-Chiro-Inositol (DCI) supplementation (controls). A subgroup analysis was performed to evaluate selected outcomes in PCOS and non-PCOS women.Results: We included 8 studies embedding 812 participants. We found a reduction in GA (p < 0.00001) and SL (p = 0.0007) in patients receiving MI with respect to controls. MI was effective in both PCOS (p < 0.00001) and non-PCOS women (p = 0.02) in reducing GA; conversely, MI supplementation decreased the SL only in PCOS women (p < 0.00001).Conclusion: During IVF, MI is effective in both PCOS and non-PCOS women in saving gonadotropins, but reduces efficiently SL only in PCOS women. [ABSTRACT FROM AUTHOR]

The gonadotropins (Gth), follicle-stimulating hormone (Fsh) and luteinizing hormone (Lh), play central roles in gametogenesis in vertebrates. However, available information on their differential actions in teleost, especially in vivo , is insufficient. In this study, we established stable CHO-DG44 cell lines expressing long-lasting recombinant Japanese eel Fsh and Lh with extra O-glycosylation sites (Fsh-hCTP and Lh-hCTP), which were produced in abundance. Immature female eels received weekly intraperitoneal injections of Gths. Fsh-hCTP induced the entire ovarian development by 8 weeks from the beginning of injection; thus, the ovaries of most fish were at the migratory nucleus stage while the same stage was observed in eels after 4 weeks in the Lh-hCTP-treated group. In contrast, all pretreated and saline-injected eels were in the pre-vitellogenic stage. Gonadosomatic indices in the Fsh-hCTP-treated group were significantly higher than those in the Lh-hCTP group at the migratory nucleus stage because of the significantly higher frequency of advanced ovarian follicles. Ovarian mRNA levels of genes related to E2 production ( cyp11a1 , cyp17a1 , cyp19a1 , hsd3b , fshr , and lhr ) were measured using real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR). All genes were induced by both Fsh-hCTP and Lh-hCTP, with a peak at either the mid- or late vitellogenic stages. Transcript abundance of cyp19a1 and fshr in the Lh-hCTP group were significantly higher than those in the Fsh-hCTP group, whereas no difference in the expression of other genes was observed between the groups. Fluctuations in serum levels of sex steroid hormones (estradiol-17β, 11-ketotestosterone, and testosterone) in female eels were comparable in the Fsh-hCTP and Lh-hCTP groups, thus increasing toward the maturational phase. Furthermore, the fecundity of the eels induced to mature by Fsh-hCTP was significantly higher than that induced by Lh-hCTP. These findings indicate that Fsh and Lh can induce ovarian development in distinctively different modes in the Japanese eel., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Kazeto, Ito, Tanaka, Suzuki, Ozaki, Okuzawa and Gen.)

Background: Various gonadotropin preparations have been used for ovarian stimulation in intrauterine insemination (IUI). The purpose of the current study was to compare human menopausal gonadotropin (hMG) and recombinant follicle-stimulating hormone (rFSH) combined with clomiphene citrate (CC) in IUI cycles for polycystic ovary syndrome- associated infertility. Methods: In this prospective trial, couples prepared for IUI cycles were randomly allocated either to receive CC and rFSH (group A, n = 132) or CC and hMG (group B, n = 144) for ovarian stimulation. Outcomes including rates of clinical pregnancy, miscarriage, ovarian hyperstimulation syndrome, multiple pregnancy, cancellation and live birth were compared. Results: The duration of gonadotropin therapy was shorter and total doses of gonadotropins was lower in the rFSH group. The number of stimulated follicles reaching >17 mm diameter was comparable between groups, but the mean follicular diameter was significantly higher in the rFSH group. The endometrium was also significantly thicker at the time of human chorionic gonadotropin administration in the rFSH group. However, pregnancy outcomes, including the rates of clinical pregnancy, ongoing pregnancy, live birth, miscarriage, ovarian hyperstimulation syndrome and cancellation, were similar between groups. Conclusion: IUI cycles in which rFSH is administered may result in shorter duration of treatment, a lower total gonadotropin dose and better follicular and endometrial characteristics on the day of human chorionic gonadotropin injection. [ABSTRACT FROM AUTHOR]

A prospective study was designed to investigate the effects of recombinant human follicle-stimulating hormone (rhFSH) on seminal anti-Müllerian hormone (AMH) levels in men with idiopathic oligoasthenoteratozoospermia (iOAT), researching possible relationships between the seminal AMH behavior and the response to the treatment. Thirty-nine men who were candidates for intracytoplasmic sperm injection (ICSI) because of iOAT were enrolled. Patients were treated on alternately days with 150 IU of rhFSH for at least 3 months before assisted reproduction cycles. Main outcome measures were seminal AMH concentrations before and after rhFSH therapy. After treatment, 16 subjects (responders) showed an improvement in their sperm count compared to baseline (7.6 ± 2.9 vs. 19.3 #177; 7.7, p < 0.01) whereas 23 men (non-responders) experienced no sperm modifications. Baseline seminal AMH concentrations were significantly higher in responders than in non-responders (53.0 #177; 30.6 vs. 34.6 #177; 18.5, p < 0.025). Following therapy, a greater increase in AMH levels was observed in responders compared to non-responders (Δ = 24.8 #177; 36.4 vs. Δ = 6.4 #177; 11.2, p < 0.028). Seminal AMH levels significantly and positively correlated with sperm count (after rhFSH treatment rho = 0.647, p < 0.001). Our study suggests that rhFSH improves sperm count in a quota of iOAT men, and the subjects who respond to the treatment have higher baseline seminal AMH concentrations than the patients who are not responsive. Seminal AMH could be helpful to select those infertile men who may benefit from rhFSH treatment. [ABSTRACT FROM AUTHOR]

Aims: To determine the efficacy of letrozole alone or with recombinant follicle-stimulating hormone (rFSH) for ovarian induction in anovulatory women. Methods: A total of 322 patients undergoing intrauterine insemination (IUI) were included in this retrospective study. Letrozole (2.5 or 5.0 mg) was administered from days 5 to 9 of menses, alone or followed with rFSH started on day 9 until the day of human chorionic gonadotropin administration. A single IUI was performed 24 h after ovulation. Results: The number of follicles, endometrial thickness and serum estradiol levels were significantly higher in the letrozole + rFSH groups than in the letrozole-alone groups (p < 0.05), but no significant difference was found between the two doses of letrozole, whether alone or with rFSH. Women treated with 5.0 mg/day of letrozole + rFSH required a total dose of rFSH similar to women treated with 2.5 mg/day of letrozole + rFSH (230.77 ± 118.29 vs. 258.55 ± 130.13 IU, respectively; p = 0.205). There was no significant difference in pregnancy rates between the two doses of letrozole, whether alone or with rFSH. Conclusion: Treatment with letrozole + rFSH was more efficacious than letrozole alone for pregnancy in the IUI program; however, the effect of 5.0 mg/day of letrozole versus 2.5 mg/day of letrozole on ovulation was equivalent, regardless of whether rFSH was used. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

STUDY QUESTIONS: Does luteinizing hormone (LH) supplementation improve live birth rate after in vitro fertilization (IVF) in patients aged ≥ 35 years receiving a gonadotrophin-releasing hormone (GnRH) antagonist protocol? SUMMARY ANSWER: There was no difference in live birth rate with use of LH during IVF in patients aged ≥ 35 years undergoing IVF treatment using a GnRH antagonist protocol. WHAT IS KNOWN ALREADY: Use of GnRH analogues as part of a controlled ovarian hyperstimulation protocol during IVF treatment cycles decreases the amount of LH available to developing follicles. The role of LH supplementation for improving outcomes in patients undergoing controlled ovarian hyperstimulation as part of assisted reproduction treatments, particularly those involving a GnRH antagonist protocol, is unclear. It has been suggested that higher risk patients (e.g. age ≥ 35 years, poor ovarian reserve) may benefit from LH supplementation. STUDY DESIGN, SIZE, DURATION: This single-centre, randomized controlled trial was conducted from 1 October 2012 to 30 June 2014. A total of 240 women aged ≥ 35 years undergoing IVF received ovarian stimulation using a GnRH antagonist protocol, with recombinant follicle-stimulating hormone (r-FSH; Gonal-F®) starting from cycle day 2 or 3. GnRH antagonist (Cetrotide®) was administered on Day 5 of r-FSH administration. On Day 6, patients in the LH supplementation group were switched to r-FSH/r-LH (Pergoveris®) 150/75 IU/day. Randomization to study treatments was performed in blocks of 4 via a computer-generated random number list. PARTICIPANTS/MATERIALS, SETTING, METHODS: Of the 240 patients randomized to treatment, 120 received r-FSH/r-LH and 120 received r-FSH. Patients were recruited from the IVFAS, An Sinh Hospital, Ho Chi Minh City, Vietnam. MAIN RESULTS AND THE ROLE OF CHANCE: Live birth rate did not differ significantly (P . 0.05) between r-FSH/r-LH and r-FSH recipients (16.7 versus 17.5%; between-group difference 0.8,95% confidence interval [CI] 29.5, 1 1.2). In addition, there were no significant differences between the r-FSH/r-LH and r-FSH groups with respect to the number of oocytes retrieved, implantation rate, miscarriage rate and clinical pregnancy rate. LIMITATIONS, REASONS FOR CAUTION: The open-label design could have introduced bias, and the relatively small sample size may have allowed detection of only the most common adverse events. In addition, the study was likely to be underpowered based on differences between the response rate assumptions used in the sample size calculation and the actual response rate during the study. WIDER IMPLICATIONS OF THE FINDINGS: The results of this study found no additional benefit from adding LH supplementation to ovarian stimulation with aGnRH antagonist protocol in women aged > 35 years, and add to the body of evidence in this area. However, findings across studies are still inconsistent and additional research is needed before any clear recommendations for clinical practice can be made. STUDY funding/competing interests: This study was supported by the Research Center for Genetics and Reproductive Health, School of Medicine, Vietnam National University HCMC. The authors state that they have no financial or commercial conflicts of interest. [ABSTRACT FROM AUTHOR]

Objectives: To analyze the expression of protein markers related to cell proliferation and death, as well as oestrogen and progesterone receptors in the endometrium of infertile women with hypothalamic-pituitary dysfunction treated with clomiphene citrate (CC) or recombinant follicle-stimulating hormone (rFSH), and compare them with ovulatory women.Study Design: The study included 12 control ovulatory women and 29 anovulatory women, 19 of whom underwent ovulation induction with CC (n = 12) or rFSH (n = 5). Endometrial biopsies were obtained by Pipelle during the mid-secretory phase. Samples were stained with haematoxylin and eosin. Immunohistochemistry of proteins related to cell proliferation and cell death, as well as steroid receptors, was undertaken, and apoptosis was determined using TUNEL analysis.Results: Immunohistochemical analysis of Ki67 expression showed significantly higher expression in the glandular epithelium of ovulatory women compared with the other groups. Glandular oestrogen receptor α expression was significantly lower in rFSH-treated women compared with ovulatory women. The number of apoptotic cells, Bax expression and progesterone receptor expression were similar in all groups. In contrast, Bcl-2 expression was significantly lower in the glandular epithelium of rFSH-treated women.Conclusions: In infertile women with hypothalamic-pituitary dysfunction, treatment with ovulation-inducing agents modifies the expression of proteins involved in cell proliferation and death, as well as the expression of steroid hormone receptors in the endometrium. These differences may help to explain, at the molecular level, the functionality of the endometrium during the implantation window, and may help to optimize pregnancy rates obtained with these treatments. [ABSTRACT FROM AUTHOR]

Objective: To compare two different gonadotropin preparations, human menopausal gonadotropin (hMG) and recombinant follicle-stimulating hormone (rFSH), combined with clomiphene citrate (CC) in women with unexplained infertility undergoing intrauterine insemination (IUI). Study design: In this prospective clinical trial, couples prepared for IUI cycles were randomly allocated to two groups either to receive CC and hMG (group A, n =127) or CC and rFSH (group B, n =132) for ovarian stimulation. Outcomes including rates of clinical pregnancy, miscarriage, OHSS, multiple pregnancy, cancelation, and live birth were compared between groups. Results: Duration of gonadotropin therapy was significantly shorter in group B (5.1±0.84 vs. 4.7±0.8 days, CI=95%, P <0.001). The total dose of administered gonadotropin was also significantly lower in group B (386.9±68.2 vs. 348.2±56.3IU, CI=95%, P <0.001). Dominant follicle number (>17mm), mean follicular diameter, and endometrial thickness on the day of hCG injection were similar. Clinical pregnancy, multiple pregnancies, abortion, live birth, ovarian hyperstimulation syndrome (OHSS), and cancelation rates were not statistically different between the groups. Conclusion: IUI cycles in which rFSH had been administered may require shorter duration and a lower total gonadotropin dose. [ABSTRACT FROM AUTHOR]

Follicle development is controlled amongst other factors by pituitary gonadotropins follicle-stimulating hormone (FSH) and luteinizing hormone (LH) that act in synergy in completing follicle maturation. Exogenous gonadotropins, combined with gonadotropin-releasing hormone agonists, have been successfully used in patients with ovulatory disorders undergoing assisted reproduction. There is some evidence of a beneficial role of androgens or LH administration before FSH stimulation. This study was designed to verify whether the addition of LH in the early follicular phase, in downregulated patients undergoing follicular stimulation for assisted reproduction, would add benefits in terms of general outcomes and pregnancy rates. We compared two groups of patients one of which was treated with recombinant FSH (rFSH) alone and the other with rFSH plus recombinant LH (rLH), in the early follicular phase only. The number of eggs recovered was higher in the group treated with FSH only; however, the number of embryos available at transfer was similar in the two groups and, more importantly, the number of Grades I and II embryos was higher in the group pretreated with LH. Similarly, although biochemical pregnancy rate and clinical pregnancy rates were similar in both groups, a beneficial role of LH priming was demonstrated by the higher implantation rate achieved in these patients. [ABSTRACT FROM AUTHOR]

Objectives: This study compares the efficacy and patient tolerance of follitropin-β (recagon) administered using a pen device with conventional syringe in infertile couples undergoing in vitro fertilization/intracytoplasmic sperm injection treatment. Methods: Data for 481 patients were retrieved retrospectively for the analysis. Conventional syringe group constituted 204 patients with 217 cycles and 265 patients with 294 cycles in the pen-device group. Down-regulation was achieved with GnRH agonist. Results: Comparison of follitropin-β administered with pen and syringe showed the following data, respectively. A total dose of 1909·38/2100·65 IU ( P < 0·001), duration of stimulation, 9·70/10·47 days ( P < 0·05), oestradiol levels on the day of human chorionic gonadotropin, 1488·34/1067·63 pg/ml, number of follicles reaching >16-mm size, 9·75/7·34 ( P < 0·05), number of oocytes retrieved, 13·84/9·55 ( P < 0·001) and number of embryos available for freezing, 4·56/1·30 ( P < 0·05), the above data were observed in pen/conventional syringe groups, respectively. The live birth rates per cycle were 28·85% and 30·95% in the conventional syringe/pen-device groups, respectively. Patient tolerance with respect to pain at injection site was better with the pen device ( P < 0·025). Conclusion: The data show that follitropin-β administered with pen device is well tolerated and more efficacious with respect to ovarian stimulation outcome compared with the conventional syringe. [ABSTRACT FROM AUTHOR]

Aim: The mild ovarian stimulation protocol for in vitro fertilization (IVF) is carried out to minimize adverse side-effects as well as cost. While performing mild ovarian stimulation with a gonadotropin-releasing hormone (GnRH) antagonist, the pregnancy rate was examined in cases that exhibited a serum estradiol (E2) drop down. Methods: In this study, 174 patients who requested mild ovarian stimulation for IVF began clomiphene citrate on day 3 and recombinant follicle-stimulating hormone (FSH) on day 5 of their menstrual cycles. A GnRH antagonist was administered when the dominant follicle reached a diameter of 14 mm. Serum luteinizing hormone and estradiol were measured at the time of GnRH antagonist administration and at the time of human chorionic gonadotropin (hCG) injection. Pregnancy rates and implantation rates were compared between 24 cycles in which the E2 level fell at the time of hCG injection and 150 cycles in which it did not fall. Results: The pregnancy rate in the cases in which the E2 level fell (25% decrease) at the time of hCG injection was significantly lower than it was in the cases in which it did not fall (16.7 vs 41.0%). The implantation rate for the cases in which the E2 level fell was also lower than that of the control group (7.0 vs 31.0%). There was no significant difference in the number of good-quality embryos between the two groups. Conclusion: When performing the mild ovarian stimulation protocol, serum E2 should be followed. It is prudent to avoid embryo transfer in the same cycle in cases that exhibit E2 drop down. (Reprod Med Biol 2008; 7: 85–89) [ABSTRACT FROM AUTHOR]

Aim. To compare the clinical pregnancy rate in recipients of oocytes from donors treated with leuprorelin + human menopausal gonadotropins (hMG) with that obtained when the donors were treated with ganirelix + recombinant follicle-stimulating hormone (rFSH). The secondary aim was to compare the donors' response to the two treatments. Method. A prospective, randomized, comparative study was conducted between January 2005 and November 2006 in a private hospital. Donors were randomized to receive a long protocol of leuprorelin + hMG (group DI) or ganirelix + rFSH (group DII). Their respective recipients were randomized to group RI or group RII, respectively. Results. The characteristics of the donors were similar in both groups. More cycles were cancelled in group DI than in group DII (28.1% vs. 2.5%; p < 0.05). Compared with donors in group DII, the donors in group DI required a significantly higher dose of gonadotropins (2794 ± 957 U vs. 1777 ± 1043 U; p < 0.05) and more days of stimulation (11.7 ± 2.3 vs. 9.5 ± 1.5; p < 0.05); they also yielded fewer oocytes (15.0 ± 6.1 vs. 17.9 ± 8.6; p < 0.05). There were no differences in the characteristics of the recipients, in the fertilization rate or in the number of embryos transferred. The quality of transferred embryos was better in group RI (8.0 ± 1.2 vs. 7.5 ± 1.6; p < 0.05), and this group also achieved a better pregnancy rate per embryo transfer than did group RII (62.3% vs. 48.4%; p < 0.05). Conclusions. Treating oocyte donors with leuprorelin + hMG produces among recipients a greater probability of clinical pregnancy per embryo transfer than when donors are treated with ganirelix + rFSH; however, more cycles are cancelled and the former treatment is more unpleasant for donors. [ABSTRACT FROM AUTHOR]

Objective. Recently we proposed a randomized trial specifically designed to evaluate the cost-effectiveness of two different protocols of stimulation in intrauterine insemination (IUI) cycles. Computer-simulated clinical models have been developed to perform pharmacoeconomic studies, creating a decision tree in which the complex procedure is performed and repeated. The present study was designed to compare the cost-effectiveness of recombinant follicle-stimulating hormone (rFSH) and human-derived FSH (hFSH) in ovarian stimulation and to indicate which protocol should be used in IUI cycles. Study design. Two computer-generated decision tree models were constructed to compare the clinical effects and costs of rFSH versus hFSH in IUI cycles. A first decision tree model was built according to the trial previously published. In a second model, 10 000 hypothetical infertile patients were entered in a computer-generated simulation and were stimulated with two different protocols for IUI. IUI was hypothetically performed in both groups of patients with a known pregnancy, cancellation, miscarriage and abandonment rate. The two protocols were compared using a cost-effective analysis: cost-effectiveness ratios (CE) and incremental cost-effectiveness ratios (ICER) were calculated. The cost-effectiveness acceptability curve (CEAC) was constructed. Results. The overall estimated costs with each ovarian stimulation strategy in the first model demonstrated that rFSH was a less cost-effective strategy, with an ICER of [euro]13 727. The CEAC showed that at a level of [euro]0 of willingness to pay, hFSH was cost-effective in 73% of the samples while rFSH was cost-effective in 27% only. Recombinant FSH would be more cost-effective than hFSH at an effectiveness threshold of 0.170 and at a cost per cycle of [euro]235. This finding was also confirmed by the acceptability curve obtained with 10 000 Monte Carlo simulations, in which hFSH was cost-effective in about 96-98% of samples at any threshold of willingness to pay. Conclusions. This study represents the first statistical model developed with a computer-generated clinical simulation with the intent to elaborate a pharmacoeconomic comparison between rFSH and hFSH in ovarian stimulation for IUI cycles. Results demonstrated that hFSH is more cost-effective than rFSH. [ABSTRACT FROM AUTHOR]

The renewed interest in luteinizing hormone (LH), together with limited and decreasing health resources, make essential the comparison of high-cost, recombinant follicle-stimulating hormone (rFSH) preparations (devoid of LH) and human menopausal gonadotropin (hMG) in terms of clinical efficacy. All published, randomized controlled trials (RCTs) comparing rFSH versus hMG under different protocols of stimulation were examined. Eight true RCTs were included in this meta-analysis, recruiting 2031 participants. Data for ongoing pregnancy/live birth rate, clinical pregnancy rate, miscarriage rate, multiple pregnancy rate and ovarian hyperstimulation syndrome (OHSS) were extracted, and odds ratios (ORs) and 95% confidence intervals (CIs) were calculated with the use of a fixed-effects model. Data for the meta-analysis were combined using RevMan software (using the Mantel–Haenszel method). Pooling the results of these RCTs showed no significant difference between rFSH and hMG regarding the different outcomes: ongoing pregnancy/live birth rate, OR 1.18 (95% CI 0.93–1.50); clinical pregnancy rate, OR 1.2 (95% CI 0.99–1.47), miscarriage rate, OR 1.2 (95% CI 0.70–2.16); multiple pregnancy rate, OR 1.35 (95% CI 0.96–1.90); incidence of moderate/severe OHSS, OR 1.79 (95% CI 0.74–4.33). However, there was significant reduction in the amount of gonadotropins in favor of hMG over rFSH. There was no significant heterogeneity of treatment effect across the trials. In conclusion, there is no clinically significant difference between hMG and rFSH in in vitro fertilization/intracytoplasmic sperm injection cycles. Decision-makers should establish their choice of one drug over the other based on the most up-to-date evidence available. [ABSTRACT FROM AUTHOR]

: ObjectiveTo compare the efficacy of recombinant FSH and urinary-derived hMG for ovarian stimulation during IVF.: DesignRetrospective analysis of data from IVF cycles conducted over 15 months.: SettingUniversity hospital IVF unit.: Patient(s)Three hundred twenty-four women undergoing their first to sixth IVF cycle.: Intervention(s)After pituitary down-regulation, patients received recombinant FSH or hMG, according to personal choice. After hCG administration, patients underwent oocyte retrieval, oocyte fertilization, and embryo transfer.: Main outcome measure(s)Implantation rate and clinical ongoing pregnancy rate per oocyte retrieval.: Result(s)Patients who chose recombinant FSH were slightly younger than those who chose hMG (34.1 vs. 35.1 years, respectively). Although more embryos were transferred in the hMG group (3.6 vs. 3.2), the ongoing pregnancy and implantation rates were significantly higher in the recombinant FSH group (ongoing pregnancy rate, 50.0% vs. 36.2%).: Conclusion(s)Recombinant FSH is more effective than hMG for ovarian stimulation in IVF cycles. This increased efficacy, which is achieved with fewer ampoules, is likely to offset the higher acquisition costs of recombinant FSH. [Copyright &y& Elsevier]

: ObjectiveTo carefully examine the features of controlled ovarian stimulation performed with recombinant FSH-α or hMG.: DesignControlled, prospective, randomized comparison of fixed gonadotropin regimens.: SettingAcademic research institution.: Patient(s)Fifty infertile patients who were candidates for IUI.: Intervention(s)Patients were randomized to receive a fixed regimen of recombinant FSH-α (150 IU/day, 25 patients) or hMG (150 IU/day, 25 patients), after GnRH-agonist suppression (long regimen).: Main outcome measure(s)Daily measurements of serum LH, immunoreactive FSH, hCG, E2, P, and T. Transvaginal pelvic ultrasound every 2 days. Pregnancy and abortion rates. Cost of medications.: Result(s)Two recombinant FSH-α-treated patients did not respond. Despite matched daily FSH dose, duration of treatment (hMG 10.8 ± 0.4 vs. recombinant FSH-α 12.4 ± 0.5 days), gonadotropin dose (21.7 ± 0.8 vs. 25.3 ± 1.3 ampoules), gonadotropin cost (288 ± 10 vs. 1,299 ± 66 €/cycle), serum P levels, and small preovulatory follicle number were significantly lower, and LH, hCG, immunoreactive FSH levels, and larger follicles on day 8 were significantly higher in hMG-treated patients. The pregnancy, abortion, and twin pregnancy rates did not differ.: Conclusion(s)The hMG administration was associated with: [1] increased serum LH activity and immunoreactive FSH levels during treatment; [2] reduced signs of premature luteinization; [3] differential modulation of folliculogenesis; [4] lower treatment duration, gonadotropin dose, and cost; and [5] clinical outcome comparable to recombinant FSH-α. [Copyright &y& Elsevier]

Background: We studied polycystic ovarian syndrome (PCOS) in fifty 25- to 37-year-old women who failed to conceive with clomiphene citrate treatment. Methods: Twenty patients were submitted to treatment with low-dose (75 IU) urinary FSH (uFSH) in order to achieve ovulation and 30 patients were treated with recombinant FSH (rFSH) according to the same protocol. Results: Ovulation was achieved in 75 and 97% of the cycles after uFSH and rFSH, respectively (p < 0.02). The length of treatment needed to achieve ovulation, the number of ampules given and dose per kilogram were significantly lower in the rFSH group. Mild ovarian hyperstimulation syndrome (OHSS) was observed in 9 uFSH cycles, whereas only 1 of the women treated with rFSH developed an OHSS (1/38 vs. 9/36; p < 0.01). Conclusion: rFSH is more efficient than uFSH in inducing ovulation in PCOS patients. The high prevalence of ovulatory cycles using a lower dose guaranteed greater safety of treatment and significantly reduced the incidence of OHSS.Copyright © 2001 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Abstract Background Gonadotropins are used in ovulation induction (OI) for patients with anovulatory infertility. Pharmacologic OI is associated with risks of ovarian hyperstimulation syndrome and multiple pregnancy. Treatment protocols that minimize these risks by promoting monofollicular development are required. A starting dose of 37.5 IU/day follitropin alfa has been used in OI, particularly among women at high risk of multifollicular development and multiple pregnancy. A retrospective case series study was performed to evaluate rates of monofollicular development and singleton pregnancy following standard treatment with 37.5 IU/day follitropin alfa. Methods Spanish centers that had performed at least five OI cycles during 2008 using 37.5 IU/day follitropin alfa as a starting dose were invited to participate. Data could be provided from any cycle performed in 2008 (up to a maximum of 12 consecutive cycles per site). Case report forms were collected during April-November 2009 and reviewed centrally. Descriptive statistics were obtained from all cases, and follicular development and clinical pregnancy rates assessed. Potential associations of age and body mass index with follicular development and clinical pregnancy were assessed using univariate correlation analyses. Results Thirty centers provided data on 316 cycles of OI using a starting dose of 37.5 IU/day follitropin alfa. Polycystic ovary syndrome was the cause of anovulatory infertility in 217 (68.7%) cases. Follitropin alfa at 37.5 IU/day was sufficient to achieve ovarian stimulation in 230 (72.8%) cycles. A single follicle ≥16 mm in diameter developed in 193 cycles (61.1%; 95% confidence interval [CI] 55.7-66.4%). Seventy-eight women (24.7%; 95% CI 19.9-29.5%) became pregnant: 94.9% singleton and 5.1% twin pregnancies. Fourteen started cycles (4.4%) were cancelled, mainly due to poor response. Univariate correlation analyses detected weak associations. Conclusions Monofollicular growth rate was comparable with optimal rates reported elsewhere and the pregnancy rate exceeded that in other studies of OI using gonadotropins. A starting dose of 37.5 IU/day follitropin alfa is an effective option in selected cases to prevent ovarian hyper-response without loss of efficacy. The analysis could not identify a single selection criterion for individuals who would benefit from this treatment approach; this merits further investigation in prospective studies.

• Six recombinant Japanese eel Gths were produced using the HEK293 expression system. • All the recombinant Gths were N-glycosylated in comparable degree while only rGth-hCTPs and rGth-eCTPs were O-glycosylated. • The rGth-hCTPs were O-glycosylated and sialylated more highly than rGth-eCTPs. • The rGth-hCTPs induced steroidogenesis and spermatogenesis effectively in immature male Japanese eel. Gonadotropins (Gths), follicle-stimulating hormone (Fsh), and luteinizing hormone (Lh) play central roles in the reproductive biology of vertebrates. In this study, recombinant single-chain Japanese eel Gths (rGth: rFsh and rLh), and recombinant chimeric Gths (rGth-hCTPs: rFsh-hCTP and rLh-hCTP; rGth-eCTPs: rFsh-eCTP and rLh-eCTP) with an extra O-glycosylation site (either a C-terminal peptide of human (hCTP) or equine (eCTP) chorionic gonadotropin), which are known to prolong the half-life of glycoprotein were produced in HEK293 cells and highly purified. Lectin blot analyses demonstrated that all these recombinant Gths contained N-glycans of the high mannose and complex types. In contrast, only rGth-hCTPs and rGth-eCTPs possessed highly sialylated O-linked oligosaccharides. Further analyses of glycans by liquid chromatography-mass spectrometry suggested that the species, amount, and degree of sialylation of N-glycans were comparable among recombinant Fshs and recombinant Lhs, while the amount of O-glycans with sialic acids in rGth-hCTPs was higher than that in the corresponding rGth-eCTPs. The serum levels of recombinant Gths in male eels significantly increased 12–24 h after a single injection of the Gths. The levels of rGth-hCTPs tended to be higher than those of the corresponding rGths and rGth-eCTPs throughout the experimental period, coinciding with the serum fluctuations of 11-ketotestosterone (11KT). The long-term treatment of male eels with these recombinant Gths also revealed the superiority of rGth-hCTPs in assisted reproduction; thus, the serum levels of 11KT and gonadosomatic indices in eels treated with rGth-hCTPs were higher than those in eels treated with the corresponding rGths and rGth-eCTPs. The induction of the entire process of spermatogenesis was only histologically observed in rGth-hCTPs-treated eels. These findings strongly suggest that hCTP enhances the in vivo biological activity of recombinant Japanese eel Gths due to the high abundance of O-linked glycans with sialylated antennae. [ABSTRACT FROM AUTHOR]

• Compared treatment outcomes for hp-hMG and rFSH in poor ovarian response patients undergoing IVF/ICSI with GnRH antagonist protocol. • Higher serum IGF-1 level on the day of oocyte retrieval associated with hp-HMG vs rFSH might suggest a superior endocrine environment. • hp-HMG and rFSH did not lead to significantly different treatment outcomes in POR patients. Poor ovarian responders generally refer to patients who respond poorly to ovarian stimulation for assisted reproductive techniques (ART) such as in-vitro fertilization (IVF) and hence experience low live birth rate. Various controlled ovarian stimulation (COS) protocols have been developed during the past 3 decades for IVF/ICSI to improve oocyte quality and ultimately live birth rate, to increase ovarian response in POR patients, and to reduce the risk of ovarian hyperstimulation syndrome. Both highly puri?ed human menopausal gonadotropin (hp-hMG) and recombinant follicle-stimulating hormone (rFSH) have been widely used for COS during IVF/ICSI. Their in?uence on treatment outcome in women undergoing IVF/ICSI hasbeen actively debated. To compare highly purified human menopausal gonadotropin (hp-hMG) and recombinant follicle-stimulating hormone (rFSH) in patients with poor ovarian response undergoing in vitro fertilization/intracytoplasmic sperm injection with a gonadotropin-releasing hormone antagonist protocol. This retrospective cohort study included 60 patients with poor ovarian response (30 received hp-hMG and 30 received rFSH) undergoing in vitro fertilization/intracytoplasmic sperm injection with a gonadotropin-releasing hormone antagonist protocol. Pregnancy-related outcomes, ovarian response, oocyte, and embryo parameters were compared between the 2 groups. Additionally, serum insulin-like growth factor-1 and insulin-like growth factor binding protein-1 levels on the day of oocyte retrieval were compared between the 2 groups. The 2 treatments resulted in comparable numbers of oocytes retrieved and embryos, comparable oocyte retrieval rate, mature oocyte rate, and fertilization rate, and also comparable clinical pregnancy rates, implantation rates, and miscarriage rate. However, hp-hMG led to statistically insignificant higher viable embryo rate (54.0% vs 44.8%; P = 0.174) and live birth rate per pregnancy (16.7% vs 10%) versus rFSH. Finally, statistically significantly higher serum insulin-like growth factor-1 level (178.53 [13.70] ng/mL vs 164.93 [12.17] ng/mL; P = 0.01) and statistically insignificantly lower serum insulin-like growth factor binding protein-1 level (19.53 [3.56] ng/mL vs the lower insulin-like growth factor binding protein-1 level SD is (2.76 [20.83] ng/mL; P > 0.05) on the day of oocyte retrieval were associated with hp-hMG versus rFSH. hp-HMG and rFSH did not lead to significantly different treatment outcomes in patients with poor ovarian response undergoing in vitro fertilization/intracytoplasmic sperm injection with a gonadotropin-releasing hormone antagonist protocol, although significantly higher serum insulin-like growth factor-1 level and insignificantly lower serum insulin-like growth factor binding protein-1 level on the day of oocyte retrieval associated with hp-HMG might suggest a beneficial endocrine environment. (Curr Ther Res Clin Exp. 2020; 81:XXX–XXX) [ABSTRACT FROM AUTHOR]

An animal mammary bioreactor is regarded as an excellent biological system which is applied to produce large-scale recombinant proteins in milk. However, there are no effective methods to produce a large amount of some pharmaceutical proteins, such as human follicle-stimulating hormone (FSH), by large animal mammary gland bioreactors due to the fact that accumulation of excessive bioactive FSH might cause serious diseases in animals. Here, we report a novel strategy of preparing recombinant human FSH (rhFSH) from goat mammary glands, which could avoid the accumulation of bioactive FSH in goats. First, the single inactive FSHα and FSHβ subunits expressed in goat mammary epithelial cells and goat mammary glands were performed to reassemble in vitro and were found to self-assemble into a complete heterodimer rhFSH at 4 °C and pH 7.4. Further, a cyclic adenosine monophosphate (cAMP) induction assay showed that the cAMP levels in cell lysate of HEK 293/FSHR cells were increased by about 8-fold in reassembled rhFSH groups than that in the control group ( P < 0.01). Pharmacokinetic analysis indicated that the reassembled rhFSH from goat mammary glands was comparable to that of the commercially available Gonal-F ( P > 0.05). In addition, the increasing dose of reassembled rhFSH significantly promoted ovulation of mouse and ovary weight gain of Sprague Dawley rat compared with the control groups and maximum values were up to 3-fold ( P < 0.01) and 2.8-fold ( P < 0.01), respectively. The reassembled rhFSH showed a similar effect to Gonal-F in inducing expression of FSH target genes in vivo and activating the PI3K pathway in granulosa cells. Our study developed a novel method to produce rhFSH and provided the basis for preparing FSH by the goat mammary gland bioreactor with less health problems on the producing animals.

Background: Poor ovarian responders generally refer to patients who respond poorly to ovarian stimulation for assisted reproductive techniques (ART) such as in-vitro fertilization (IVF) and hence experience low live birth rate. Various controlled ovarian stimulation (COS) protocols have been developed during the past 3 decades for IVF/ICSI to improve oocyte quality and ultimately live birth rate, to increase ovarian response in POR patients, and to reduce the risk of ovarian hyperstimulation syndrome. Both highly puri?ed human menopausal gonadotropin (hp-hMG) and recombinant follicle-stimulating hormone (rFSH) have been widely used for COS during IVF/ICSI. Their in?uence on treatment outcome in women undergoing IVF/ICSI hasbeen actively debated., Objectives: To compare highly purified human menopausal gonadotropin (hp-hMG) and recombinant follicle-stimulating hormone (rFSH) in patients with poor ovarian response undergoing in vitro fertilization/intracytoplasmic sperm injection with a gonadotropin-releasing hormone antagonist protocol., Methods: This retrospective cohort study included 60 patients with poor ovarian response (30 received hp-hMG and 30 received rFSH) undergoing in vitro fertilization/intracytoplasmic sperm injection with a gonadotropin-releasing hormone antagonist protocol. Pregnancy-related outcomes, ovarian response, oocyte, and embryo parameters were compared between the 2 groups. Additionally, serum insulin-like growth factor-1 and insulin-like growth factor binding protein-1 levels on the day of oocyte retrieval were compared between the 2 groups., Results: The 2 treatments resulted in comparable numbers of oocytes retrieved and embryos, comparable oocyte retrieval rate, mature oocyte rate, and fertilization rate, and also comparable clinical pregnancy rates, implantation rates, and miscarriage rate. However, hp-hMG led to statistically insignificant higher viable embryo rate (54.0% vs 44.8%; P  = 0.174) and live birth rate per pregnancy (16.7% vs 10%) versus rFSH. Finally, statistically significantly higher serum insulin-like growth factor-1 level (178.53 [13.70] ng/mL vs 164.93 [12.17] ng/mL; P  = 0.01) and statistically insignificantly lower serum insulin-like growth factor binding protein-1 level (19.53 [3.56] ng/mL vs the lower insulin-like growth factor binding protein-1 level SD is (2.76 [20.83] ng/mL; P > 0.05) on the day of oocyte retrieval were associated with hp-hMG versus rFSH., Conclusions: hp-HMG and rFSH did not lead to significantly different treatment outcomes in patients with poor ovarian response undergoing in vitro fertilization/intracytoplasmic sperm injection with a gonadotropin-releasing hormone antagonist protocol, although significantly higher serum insulin-like growth factor-1 level and insignificantly lower serum insulin-like growth factor binding protein-1 level on the day of oocyte retrieval associated with hp-HMG might suggest a beneficial endocrine environment. ( Curr Ther Res Clin Exp . 2020; 81:XXX-XXX)., (© 2019 The Author(s).)

Breast cancer patients under 40 years of age who are candidate to chemotherapy with alkylating drugs may undergo controlled ovarian stimulation (COS) with recombinant human follicle-stimulating hormone (rhFSH) in order to get fertility preservation by mature oocyte cryostorage. The direct effect(s) of exogenous rhFSH on the chemosensitivity of breast cancer is currently unknown. To clarify this issue, we incubated four different breast cancer cell lines with rhFSH (10 IU/L, 24 h) and then we exposed them to doxorubicin (DOX) or cyclophosphamide (CPA). The effect(s) of rhFSH on human breast cancer cells treated with DOX or CPA was measured in terms of (1) cell viability, (2) cytotoxicity, (3) multidrug resistance (MDR) genes and proteins expression and activities, and (4) hypoxia-inducible factor 1-alpha (HIF-1α) activation. Pretreatment with rhFSH significantly increased the viability of breast cancer cells after treatment with DOX or CPA, and reduced the lactate dehydrogenase leakage and reactive oxygen species production. Moreover, after preincubation with rhFSH, the MDR proteins (Pgp, MPR1, and BCRP) expression and activity resulted upregulated and the HIF-1α pathway activated. In addition, the use of a widely used HIF-1α inhibitor, the 3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole (YC-1), prevented the rhFSH effect on the onset of MDR. Taken together, these observations suggest that a short exposure to rhFSH induces chemoresistance to DOX and CPA in human breast cancer cells via HIF-1α activation., (© The Author(s) 2019. Published by Oxford University Press on behalf of Society for the Study of Reproduction.)