Recombinant Human Chorionic Gonadotropin Research Articles

O-074 Dual trigger is not superior to GnRH Agonist alone for final oocyte maturation in elective fertility preservation. A Randomized Controlled Trial

Abstract Study question Is Dual trigger for final oocyte maturation associated with a higher number of mature (MII) oocytes compared to GnRH-a trigger alone in elective fertility preservation? Summary answer Adding hCG to GnRH-a for triggering final oocyte maturation does not increase the number of MII oocytes in elective fertility preservation cycles. What is known already Triggering final oocyte maturation represents a key step in ovarian stimulation. In good prognosis patients undergoing oocyte cryopreservation, the current standard approach involves the administration of a single bolus of GnRH-agonist 36 hours before the pick-up. Previous studies have shown a higher number of MII oocytes when Dual Trigger (hCG+ GnRH-a) is performed, compared to recombinant human chorionic gonadotropin (rhCG) alone. Nevertheless, a notable gap exists in the literature, as no studies have investigated the potential additional benefit in final oocyte maturation when dual trigger is compared to GnRH-a alone. Study design, size, duration This is a randomized controlled superiority trial including elective oocyte cryopreservation cycles performed in a University Hospital. A total of 109 women were enrolled in this study between October 2021 to April 2023 with a 1:1 allocation. Eligible patients were ≤40 years old, with an antral follicular count (AFC)<20 and anti-Mullerian hormone (AMH)≤3ng/ml. Patients were randomized to final oocyte maturation triggering with Triptorelin 0,2mg or a dual trigger (Triptorelin 0.2 mg + 250 ug rhCG). Participants/materials, setting, methods Controlled ovarian stimulation was performed using 225-300IU/day of rFSH alfa or beta, or equivalent rFSH delta (15-20μg), tailored to ovarian reserve and BMI. LH surge was suppressed through a progestin-primed ovarian stimulation (PPOS) protocol, with oral administration of micronized progesterone (200mg daily) from the beginning of ovarian stimulation until the trigger day. The primary outcome was the number of MII oocytes. Comparisons are presented as estimated mean difference (EMD) and corresponding 90% confidence interval (CI). Main results and the role of chance Overall, 104 patients were analyzed, 51 in the Dual trigger group and 53 in the control arm (GnRH-a). We found no statistically significant differences in the number of retrieved oocytes comparing Dual Trigger group (8.71 ± 4.90) and GnRH-a group (9.51 ± 5.19). Similarly, the number of MII oocytes demonstrated no significant differences, with 6.86 ± 4.40 in the Dual Trigger group compared to 7.87±4.40 in the GnRH-a group (EMD -1.01 [90%CI: -2.44;0.43]). Exploring the hormonal profile there were no notable variations in estradiol levels (2064.60 ± 890.50 pg/ml vs. 2494.41 ± 1341.05 pg/ml), progesterone levels (7.78 ± 3.88 ng/ml vs. 8.94 ± 5.10 ng/ml), LH (56.28 ± 26.83 IU/L vs. 63.41 ± 32.50 IU/L), and FSH (31.14 ± 7.86 IU/L vs. 31.53 ± 9.89 IU/L) on the day following the trigger. Notably, neither group exhibited any case of Ovarian Hyperstimulation Syndrome (OHSS). Limitations, reasons for caution The sample size was calculated to detect differences on the number of MII oocytes. Therefore, results for secondary outcomes (number of oocytes retrieved and hormonal profile) should be interpreted with caution. Wider implications of the findings Adding hCG to GnRH-a for triggering final oocyte maturation does not confer any additional benefits in elective fertility preservation in term of MII oocytes compared to the administration of GnRH-a alone. Trial registration number NCT04992468

Single and multi-dose pharmacology of recombinant and urinary human chorionic gonadotrophin in men.

Human choriogonadotrophin (hCG) treatment of gonadotrophin-deficient infertile men uses hCG of urinary (uhCG) or recombinant (rhCG) origin, but these treatments have not been compared nor are there studies defining rhCG dosing in men. hCG products were studied in randomized cross-over single-dose studies of standard (Study 1, 1500 IU and 62.5 µg, respectively) or high (Study 2, 5000 IU and 250 µg) dose and a multi-dose population pharmacology study of hCG use. Eight (Study 1) and seven (Study 2) volunteers in cross-over and 52 gonadotrophin-deficient men in the multi-dose study MEASUREMENTS: In cross-over studies, serum testosterone (T), dihydrotestosterone (DHT) and estradiol by liquid chromatography-mass spectrometry (LCMS) and serum hCG, LH, FSH, SHBG and T (observational study) by immunoassays. After standard and high-dose injection, serum hCG and testosterone responses had similar timing and peak concentrations except for a mildly lower early (<48 h) serum testosterone with uhCG. In the multi-dosing study, both hCGs had similar pharmacokinetics (pooled half-life 5.8 days, p < .001), while serum testosterone concentrations were stable after injection and did not differ between hCG products. Bench testing verified that 20% of pens from 4/10 individuals were used inappropriately. Although hCG pharmacokinetics are not formally bioequivalent, the similar pharmacodynamic effects on serum testosterone indicatethat at the doses tested both hCGs provide comparable clinical effects. The starting dose of rhCG for treating gonadotrophin-deficient men should be 62.5 µg (6 clicks) of the rhCG pen.

Management of Normogonadotropic males with idiopathic infertility with bilateral varicocelectomy with and without intramuscular recombinant FSH and HCG course(s): A twenty-year- experience in a prospective, controlled, and randomized clinical study

This study presents a clinical prospective double-blinded study that contains three groups of infertile males with normogonadotropic oligoasthenospermia. All groups A, B, and C were operated on for their bilateral varicoceles. The first included 152 patients who were only operated for bilateral varicocele (nominated group A). The second group of 237 patients constituted those who were operated on, with fertile female partners, and whose preoperative spermogram showed a count lower than 15 million/ml and a 3-hour-motility lower than 20%. This group constituted two categories based on their treatment. Therefore, groups B and C received postoperative courses of intramuscular injections of recombinant follicle-stimulating hormone (rFSH) and human chorionic gonadotropin (HCG), i.e., group B received one course (3 months), and group C received two courses (6 months). The main objective is to determine the improvement in the postoperative seminal parameters in the different groups. The sample constituted 391 infertile males who were recruited conveniently based on their willingness to share their progress information and were also informed that they could stop their participation freely with no questions asked. In our treated patients, in both groups B and C, who received 1 or 2 courses of rFSH and HCG, spontaneous pregnancy occurred in 69 patients and 52 patients, respectively. Likewise, assisted pregnancy occurred in 28 and 19 patients, respectively. So treated males of groups B and C resulted in 91/140 (65%) and 61/96 (63.54%) live offspring, respectively.

Modified natural cycle allows a window of 7 days for frozen embryo transfer planning

Research questionShould ovulation be triggered in a modified natural cycle (mNC) with recombinant human chorionic gonadotrophin (rHCG) as soon as a mean follicle diameter of 17 mm is visible, or is more flexible planning possible? DesignThis multicentre, retrospective, observational study of 3087 single frozen blastocyst transfers in mNC was carried out between January 2020 and September 2022. The inclusion criteria included endometrial thickness ≥7 mm and serum progesterone <1.5 ng/ml. The main outcome was ongoing pregnancy rate. Secondary end-points were pregnancy rate, implantation rate, clinical pregnancy rate and miscarriage rate. The mean follicle size at triggering was stratified into three groups (13.0–15.9, 16.0–18.9 and 19.0–22 mm). ResultsThe baseline characteristics between the groups did not vary significantly for age, body mass index and the donor's age for egg donation. No differences were found in pregnancy rate (64.5%, 60.2% and 57.4%; P = 0.19), clinical pregnancy rate (60.5%, 52.8% and 50.6%; P = 0.10), implantation rate (62.10%, 52.9% and 51.0%; P = 0.05) or miscarriage rate (15.0%, 22.2%; and 25.0%; P = 0.11). Although ongoing pregnancy rate (54.9%, 46.8% and 43.1%; P = 0.02) varied significantly in the univariable analysis, it was no longer significant after adjustment for the use of preimplantation genetic testing for aneuploidies and egg donation. ConclusionsThe findings showed rHCG could be flexibly administered with a mean follicle size between 13 and 22 mm as long as adequate endometrial characteristics are met, and serum progesterone is <1.5 ng/ml. Considering the follicular growth rate of 1–1.5 mm/day, this approach could allow a flexibility for FET scheduling of 6–7 days, simplifying mNC FET planning in clinical practice.

FRI439 Spermatogenesis Induction For Hypogonadotrophic Hypogonadism In An Australian Tertiary Hospital Andrology Service

Abstract Disclosure: S. Sarlos: None. M. Herath: None. I. Sim: None. R. Upreti: None. R.I. McLachlan: None. C.A. Allan: None. Infertility affects 8-12% of couples with male factors contributing to 50% and solely responsible in 20-30% of cases. Male infertility due to hypogonadotrophic hypogonadism (HH) is amenable to medical treatment. We report a series of 23 men treated for infertility from HH (congenital n=13, acquired n=10) with a median age of 33 years. Causes included panhypopituitarism (n=11) [empty sella (n=2), adenoma (n=3), craniopharyngioma (n=1), pituitary hypoplasia (n=3), CHARGE syndrome (n=1), cranial radiotherapy (n=1)], Kallmann syndrome (n=1), thalassaemia major (n=1) and idiopathic (n=10). Urinary or recombinant human chorionic gonadotrophin (hCG) as an LH substitute was used based on established protocols. Commencing doses were 1500 IU or 62.5mcg s/cut twice weekly respectively and titrated to achieve normal serum total testosterone. Recombinant FSH was added after 6 months for persisting azoospermia. Wherever possible, men previously treated with long-acting injectable testosterone undecanoate were transitioned to transdermal testosterone for a minimum of 6 months prior to initiation of gonadotrophin therapy. There was wide variability in time to first appearance of sperm (median 16 months, range 4 - 42). In androgen treatment-naive men with acquired HH in adulthood (n=9), sperm was detected at a median 8 months (range 3 - 21 months) and for 4 men, hCG monotherapy was sufficient. For men with congenital causes of HH (n=13), time to first sperm detection was longer (median 17 months, range 12 - 42) and all required addition of FSH. In men previously treated with intramuscular testosterone (n=8), the median time to sperm appearance was 17 months (range 12-24) as compared to 13 months (5-42) in men treated with transdermal testosterone (n=6). To date, 11 of the 16 men actively seeking fertility have had children, with 7 requiring assisted reproduction. Gonadotrophin therapy is an effective fertility treatment for most men with HH. Clinicians can anticipate a longer time to spermatogenesis in men pre-treated with intramuscular androgens and those with congenital HH. Couples often move to assisted reproductive therapy, likely due to considerations such as semen quality, co-existing female factors and/or desire for prompt conception. Presentation: Friday, June 16, 2023

SAT376 Luteinizing Hormone Secretion in Hyperandrogenic Girls Taking Spironolactone or Metformin

Abstract Disclosure: C.M. Burt Solorzano: None. M. Gilrain: None. S.H. Kim: None. C.R. McCartney: None. Peri-pubertal hyperandrogenism (HA) typically relates to excess adrenal and/or ovarian androgen production in response to adrenocorticotropin (ACTH) and/or luteinizing hormone (LH), respectively. Spironolactone and metformin are commonly used medications to treat adolescent androgen excess. We examined how end-organ responsiveness and LH pulse patterns are affected by these medications in adolescents with HA. We studied free testosterone (T) levels (including baseline and peaks after ACTH and recombinant human chorionic gonadotropin [r-hCG] stimulation), oral glucose tolerance testing (OGTT), and 12-hr overnight LH secretion (sampled q 10 min) in post-menarcheal girls with HA before and after 3-months of either spironolactone (100 mg BID) or metformin (500 mg BID). Free T was calculated using total T (LC-MS/MS) and sex hormone binding globulin (SHBG).To date, 3 girls (aged 12-18) have been studied using spironolactone and 4 girls (aged 14-17) using metformin. (1 girl was studied twice, once with each medication.) After spironolactone treatment, free T changed by -19% (-58 to +37) (median [range]) unstimulated, by -53% (-62 to -15) after ACTH, and by -54% (-66 to +12) after r-hCG. Peak insulin level during OGTT changed by +28% (+16 to +98). Overnight LH pulse frequency changed by -64% (-89 to -10) and LH mean by -74% (-89 to -17). Two subjects in the spironolactone group demonstrated luteal LH patterns despite serum progesterone concentrations &amp;lt; 0.7 ng/mL. In the metformin group, free T changed by +35% (-32 to +125) unstimulated, by 36% (-54 to +66) after ACTH, and by 21% (-41 to +105) after r-hCG. Peak insulin level during OGTT changed by -47% (-74 to +102). LH pulse frequency changed by +10% (-29 to +22) and LH mean by +1% (-2 to +74). To summarize findings to date, mean LH and LH pulse frequency decreased in all three subjects taking spironolactone, including marked reductions in two subjects who demonstrated luteal LH patterns. While free T levels decreased in some of these girls, this seems unlikely to account for such marked changes in LH secretion. And despite similar decreases in T and also decreases in peak insulin in some girls taking metformin, LH pulse frequency did not change markedly. LH pulse patterns in two girls taking spironolactone suggest a progesterone-like effect on LH pulsatility. Spironolactone can cause irregular uterine bleeding, and canrenone (the major metabolite of spironolactone) binds to uterine progesterone receptors competitively (Fernandez MD, Br J Clin Pharm 1983). However, to our knowledge, this is the first report of LH pulse changes in HA girls using spironolactone. Further studies are needed to confirm this finding. Presentation Date: Saturday, June 17, 2023

THE ROLE OF LUTEINIZING HORMONE (LH) RECEPTOR IN THE REGULATION OF OOCYTE MATURATION: A SYSTEMATIC LITERATURE REVIEW

The hormone luteinizing hormone (LH) is an important glycoprotein hormone that controls the activity of the gonadal organs, which in turn affects the physiology of the menstrual cycle. For LH to exert its effects, its specific receptor (LHR) must be expressed by cumulus cells. Objective: To determine the role of LH receptors (Luteinizing Hormone) in the regulation of human oocyte maturation processes Method:Systematic Literature Review (SLR). Data collection was conducted by documenting all articles based on predefined inclusion and exclusion criteria. A total of 10 national and international journal articles were retrieved from databases such as Google Scholar, PubMed, and Science Direct, using specific keywords related to the role of LH receptors and oocyte maturation. The literature search and study selection process followed the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Results:The highest expression of Luteinizing Hormone Receptor (LHR) observed in preovulatory follicles. Cumulus cell maturation, covering 100% of the oocytes, was 74%. FSHR and LHR mRNA expression levels increased with an increase in LH concentration in the in vitro maturation (IVM) medium. After 24 hours of IVM, there was a significant downregulation in the expression of LHR and FSHR.The mRNA and protein levels of FSHR and LHR in the cumulus-oocyte complex gradually decreased with increasing doses of FRBI in the IVM media compared to the control group. Majority of the cumulus cells from MII oocytes had RGS2/B2M gene expression of more than 50%. LH receptor expression in granulosa cells positively correlated with morphology, oocyte maturity, and fertility rate in the poor responder group. Granulosa cells from an agonist-triggered cycle with recombinant human chorionic gonadotropin (rhCG) for 24 hours were observed to increase viability, regulate mRNA expression of 3β-HSD, LH receptor, VEGF, and BCL-L2. More than 50% of the oocytes are matured after hCG injectionat an hCG concentration of 119.8 mIU/mL. Conclusion:LH needs receptor binding and expression for proper function, resulting in improved oocyte maturation with optimal LHR concentration which is 10 µg/mL LH. LHR expression is highest in preovulatory follicles. LHR expression increases during antral follicle growth. Supplementing media with hCG improves oocyte maturity with a 77 mIU/mL cutoff value. Supplementation with FRBI reduce LHR expression in COCs. The number of cumulus cells can also indicate the level of oocyte maturity, where cumulus cells covering 100% of the oocytes show the highest oocyte maturation.

In Vitro Fertilization Outcomes With a Dual Trigger in Normoresponders in Antagonist Cycles.

Objectives To evaluate whether the dual trigger of ovulation with a gonadotropin-releasing hormone (GnRH) agonist and the standard dose of recombinant human chorionic gonadotropin (hCG) (dual trigger) is better than hCG alone in in vitro fertilization (IVF) cycles of patients who responded well to ovarian stimulation. Methods Between January 2013 and December 2021, 5593 antagonist cycles of patients were reviewed. This study included women who had an antral follicle count of 5 or more and exhibited a normoresponse to ovarian stimulation using the GnRH antagonist protocol, as determined by the follicular output rate (FORT).The primary outcome indicators consisted of the quantities of retrieved oocytes and mature oocytes. The secondary outcome markers included live birth rates, clinical pregnancy rates, and continued pregnancy rates. Results A total of 1244 normoresponder women who met the inclusion criteria were identified from the scanned files and subsequently enrolled in the GnRH antagonist protocol. A total of 383 cycles were observed in the group that was given the standard hCG triggerwhile 861 cycles were observed in the group that was given the dual trigger. The number of mature oocytes and top-quality embryos was significantly higher in the dual trigger group. The maturation rate in the hCG group was 74.8%while it was 76.9% in the dual trigger group (p=0.018). The dual trigger group exhibited an ongoing pregnancy rate of 37.6%, whereas the hCG group had a rate of 30.1% (p = 0.02). The dual trigger group exhibited a slightly higher live birth rate (34.3% vs 29.2%, p = 0.11), although this difference did not reach statistical significance. Conclusion Dual trigger of ovulation was superior to hCG alone in terms of the number of mature oocytes yielded, top quality of embryos, maturation rates, andongoing pregnancy in IVF cycles of normoresponders having ovarian stimulation on the GnRH antagonist protocol.

Human chorionic gonadotropin levels after ovulation triggering as predictors of clinical pregnancy after intracytoplasmic sperm injection: a prospective cohort study

ABSTRACT This study aimed to assess the correlation between human chorionic gonadotropin (HCG) levels after ovulation triggering and clinical pregnancy following intracytoplasmic sperm injection (ICSI), affected by HCG formulation and dose. The study was a prospective cohort study of 100 women who underwent ICSI and controlled ovarian stimulation (COS) using a fixed gonadotropin-releasing hormone (GnRH) antagonist protocol. Women were divided according to the type of ovulation triggering into three groups: (1) urinary HCG (uHCG) group (n = 33); (2) recombinant HCG (rHCG) group (n = 33); and (3) dual trigger group (n = 34). The three groups were compared to each other taking into consideration the HCG levels and their correlations to clinical pregnancy following ICSI. Clinical pregnancy could be predicted by serum HCG levels 34 h after ovulation triggering by uHCG, rHCG and dual trigger at cutoff levels of 73.72, 57.35 and 22.37 mIU/ml, respectively, with sensitivities of 95%, 94.7% and 87%, and specificities of 76.9%, 92.9% and 90.9%, respectively. Follicular fluid (FF) HCG levels could predict clinical pregnancy after ovulation triggering by uHCG, rHCG and dual trigger at cutoff levels of 21.58 mIU/ml, 20.82 mIU/ml and 8.66 mIU/ml, respectively, with sensitivities of 95%, 94.7% and 91.3%, and specificities of 92.3%, 92.9% and 90.9%, respectively. In conclusion, serum and FF HCG levels after ovulation triggering could predict clinical pregnancy following ICSI at variable cutoff levels according to HCG formulation and dose.

Does dual trigger improve euploidy rate in normoresponder? A cross-sectional study.

With the introduction of the dual triggering-gonadotropin-releasing hormone (GnRH) analog and recombinant human chorionic gonadotropin (hCG) combination, women with a history of low mature oocyte proportion and empty follicle syndrome were shown to benefit from the dual trigger. To investigate whether dual triggering of oocyte maturation with a GnRH agonist (GnRHa) combined with hCG can affect the euploidy rate and improve in vitro fertilization outcomes for normoresponder women. In this cross-sectional study, 494 women who underwent controlled ovarian stimulation with hCG (n = 274) or dual triggering (hCG+GnRHa, n = 220) at Acibadem Maslak hospital, Assisted Reproductive Unit, from January 2019-2022 were enrolled in this study. Preimplantation genetic testing for aneuploidy was performed on all participants. Both groups had similar baseline and clinical characteristics. Of the 881 embryos biopsied, 312 (35.4%) were reported as euploid in the hCG trigger group; in the dual trigger group, 186 (29.8%) of 623 screening embryos were reported as euploid. The hCG group had a higher euploidy rate per biopsied embryo, although the difference was not statistically significant (31.4 26.5 vs. 26.5 33.3, p 0.05). In normoresponders, adding GnRHa for final follicular maturation to hCG did not improve the euploidy rate.

Factors Affecting the Success Rate of Intrauterine Insemination in the Treatment of Subfertility Following Controlled Ovarian Hyperstimulation

Objectives: To determine the success rate of Intrauterine Insemination following Controlled Ovarian Hyperstimulation inpatients with subfertility and to determine the frequency of prognostic factors affecting the success rate of this treatment modality.&#x0D; Study Design: Cross-sectional study.&#x0D; Place and Duration of Study: Department of Obstetrics &amp; Gynecology, Pak-Emirates Military Hospital, Rawalpindi Pakistan, rom Feb to Aug 2019.&#x0D; Methodology: A total number of 135 sub-fertile patients, aged 18 to 40 years, with a duration of subfertility &gt; 2 years, were included in the study. Couples with bilateral tubal blockade, smoking, combined male and female factor infertility and previous ovarian surgery were excluded. Controlled ovarian hyperstimulation was done with Clomiphene Citrate for five days, followed by ovulation triggered by recombinant human chorionic gonadotropin (HCG) and standard insemination with a prepared sample of the husband’s semen after 36 hours.&#x0D; Results: Success of the procedure was seen in 23(17.04%) patients, while the remaining 112(82.96%) were unsuccessful. The mean age was 29.20±4.90 years. Of 135 patients, 83(61.48%) had primary subfertility, and 52(38.52%) had secondary subfertility. The mean duration of subfertility was 5.60±3.35 years. The mean basal FSH was 5.76±2.54 IU/l. The mean number of IUI cycles was 1.39±0.49.&#x0D; Conclusion: This study concluded that the success rate of intrauterine insemination following controlled ovarian hyperstimulation in the treatment of subfertility was 17.04%, and the duration and type of subfertility, aetiology of subfertility, basal Follicle-stimulating hormone levels and the number of Intrauterine insemination cycles are the prognostic factors affecting the success of the procedure.

Characterization of beta subunit variants of recombinant human chorionic gonadotrophin

Human chorionic gonadotropin (hCG), an endogenous glycoprotein hormone, has been widely used for the treatment of infertility and corpus luteum defect in women. The biological specificity of hCG is essentially determined by its beta (β-) subunit, whereas the alpha (α-) subunit is a common subunit shared among the gonadotropin family. In development of a therapeutic recombinant hCG, the purity analysis showed that the beta (β-) subunit has two variants, β1 and β2. Structural characterization using a combination of analytical techniques has demonstrated that β1-subunit is derived from non-glycosylation at Asn 13, whereas β2-subunit is a normal species with complete N-glycosylation at both Asn 13 and Asn 30. In vivo Bioactivity evaluation of the r-hCG fractions with various ratios of β1-and β2-subunits showed that incomplete glycosylation at Asn 13 potentially reduced the biological activity of r-hCG to promote uterus growth. Although hCG has a long history of medicinal use, this is the first report to identify the structural difference of hCG β-subunit variants, as well as to preliminary establish the structure-activity relationship of this variation. The obtained results also suggest the importance of variant characterization and necessary quality control of product variants during the development of recombinant protein therapeutics.

Comparison of dual-trigger and human chorionic gonadotropin-only trigger among polycystic ovary syndrome couples who underwent controlled ovarian stimulation and intrauterine insemination: A retrospective cohort study.

The dual-trigger regime, consisting of gonadotrophin releasing hormone agonist and human chorionic gonadotropin (HCG), has been shown to offer advantage over the HCG-only trigger regime. However, little is known about the influence of dual-trigger or HCG-only trigger regime on the reproductive outcome of polycystic ovary syndrome (PCOS) couples undergoing controlled ovarian stimulation (COS) and intrauterine insemination (IUI). A total of 404 cycles of COS and IUI treatments from couples with PCOS were enrolled, and divided, according to the regime of trigger, into dual-trigger group (n = 109, 0.1-0.2 mg gonadotrophin releasing hormone agonist plus 6000 IU HCG) and HCG-only group (n = 295, 10,000 IU HCG or 250 μg recombinant HCG). Baseline characteristics of the 2 groups were comparable (all P > .05). In dual-trigger group, live birth rate, clinical pregnancy rate and β -HCG positive rate were all higher as compared to the HCG-only group (20.18% vs 18.98%, 25.69% vs 23.39% and 28.44% vs 25.08% respectively), despite the differences failed to achieve statistical significances (all P > .05). Moreover, early miscarriage rate and multiple pregnancy rate of the dual-trigger group were lower than those of the HCG-only group (17.86% vs 18.84% and 3.57% vs 7.25% respectively), although no statistical significances were found (all P > .05). Additionally, logistic regression analysis revealed that age contributed significantly to the live birth of couples with PCOS ( P = .043, OR = 0.900). Dual-trigger regime for oocyte maturation seems to associate with beneficial improvements in reproductive outcomes of PCOS couples undergoing COS and IUI. Instead of HCG-only trigger, dual-trigger regime might be an alternative option in COS and IUI cycles for couples with PCOS.

Recombinant human chorionic gonadotropin and gonadotropin-releasing hormone agonist differently affect the profile of extracellular vesicle microRNAs in human follicular fluid.

To compare the expression profile of extracellular vesicle microRNAs (EV-miRNAs) derived from follicular fluid after a trigger with recombinant human chorionic gonadotropin (r-hCG) or with a gonadotropin-releasing hormone GnRH agonist (GnRH-a) for final oocyte maturation. A retrospective analysis of a prospective cohort. Women undergoing in vitro fertilization at a tertiary university-affiliated hospital were recruited between 2014 and 2016. EV-miRNAs were extracted from the follicular fluid of a single follicle, and their expression was assessed using TaqMan Open Array®. Genes regulated by EV-miRNAs were analyzed using miRWalk2.0 Targetscan database, DAVID Bioinformatics Resources, Kyoto-Encyclopedia of Genes and Genomes (KEGG), and Gene Ontology (GO). Eighty-two women were included in the r-hCG trigger group and 9 in the GnRH-a group. Of 754 EV-miRNAs screened, 135 were detected in at least 50% of the samples and expressed in both groups and were further analyzed. After adjusting for multiple testing, 41 EV-miRNAs whose expression levels significantly differed between the two trigger groups were identified. Bioinformatics analysis of the genes regulated by these EV-miRNAs showed distinct pathways between the two triggers, including TGF-beta signaling, cell cycle, and Wnt signaling pathways. Most of these pathways regulate cascades associated with apoptosis, embryo development, implantation, decidualization, and placental development. Trigger with GnRH-a or r-hCG leads to distinct EV-miRNAs expression profiles and to downstream biological effects in ovarian follicles. These findings may provide an insight for the increased apoptosis and the lower implantation rates following GnRH-a trigger vs. r-hCG in cases lacking intensive luteal phase support.

Comparative Effects of Human Chorionic Gonadotropin and Recombinant Luteinizing Hormone Supplementation during the Late Follicular Phase

In selected patients, addition of LH activity can improve the outcome of ovarian stimulation. Two common LH activity supplementation strategies are recombinant human LH (rLH) and human chorionic gonadotropin (hCG). The respective effectiveness of hCG versus rLH using various daily dosages and modes of administration is still discussed. In this study, we compared the outcomes of hCG versus rLH supplementation among patients with slow response to recombinant follicle stimulating hormone (rFSH).

Hormonal changes in consecutive clomiphene citrate stimulation cycles and their effect on pregnancy rates.

Objective:To determine the relationship between the cumulative effect of sequential clomiphene citrate (CC) treatments in unexplained infertile women with intercycle and intracycle serum hormone changes.Materials and Methods:Patients who received CC 50 mg in the first cycle (group I, n=34) as ovulation induction and those who received CC 50 mg in the second consecutive cycle (group II, n=18) were compared. Basal (cycle days 2-5) and trigger day (the day that recombinant human chorionic gonadotropin is given) levels of gonadotropin and steroid hormones were measured.Results:The 17OHP increase on trigger day was found to be statistically significantly higher in group II compared to the basal day (p=0.083). The testosterone (T) response on the trigger day of the patients in group II was found to be statistically significantly higher than that in group I (p=0.023). The number of selected follicles was negatively correlated with a follicle-stimulating hormone decrease and positively correlated with an estradiol increase. Endometrial thickness was positively correlated with a luteinizing hormone increase, and cycle cancelation was positively correlated with decreased estradiol.Conclusion:Based on this study, it was concluded that the reason for the increased efficiency rate in successive cycles of CC may be the cumulative increase in T and 17OHP levels. However, this result was found not to affect the clinical pregnancy rate.

Recombinant human chorionic gonadotropin induces signaling pathways towards cancer prevention in the breast of BRCA1/2 mutation carriers.

Strategies for breast cancer prevention in women with germline BRCA1/2 mutations are limited. We previously showed that recombinant human chorionic gonadotropin (r-hCG) induces mammary gland differentiation and inhibits mammary tumorigenesis in rats. The present study investigated hCG-induced signaling pathways in the breast of young nulliparous women carrying germline BRCA1/2 mutations. We performed RNA-sequencing on breast tissues from 25 BRCA1/2 mutation carriers who received r-hCG treatment for 3 months in a phase II clinical trial, we analyzed the biological processes, reactome pathways, canonical pathways, and upstream regulators associated with genes differentially expressed after r-hCG treatment, and validated genes of interest. We observed that r-hCG induces remarkable transcriptomic changes in the breast of BRCA1/2 carriers, especially in genes related to cell development, cell differentiation, cell cycle, apoptosis, DNA repair, chromatin remodeling, and G protein-coupled receptor signaling. We revealed that r-hCG inhibits Wnt/β-catenin signaling, MYC, HMGA1 , and HOTAIR , whereas activates TGFB/TGFBR-SMAD2/3/4, BRCA1, TP53, and upregulates BRCA1 protein. Our data suggest that the use of r-hCG at young age may reduce the risk of breast cancer in BRCA1/2 carriers by inhibiting pathways associated with stem/progenitor cell maintenance and neoplastic transformation, whereas activating genes crucial for breast epithelial differentiation and lineage commitment, and DNA repair.

Recombinant gonadotropin therapy to improve spermatogenesis in nonobstructive azoospermic patients – A proof of concept study

ABSTRACTPurpose:Nonobstructive azoospermia (NOA) associated with primary spermatogenic failure is a common cause of male infertility usually considered untreatable; however, some reports have suggested that hormonal stimulation to boost the intra-testicular testosterone level and spermatogenesis might increase the chance of achieving pregnancy using homologous sperm.Materials and Methods:We report a series of eight NOA males who received long-term treatment with recombinant human chorionic gonadotropin twice a week for spermatogenesis stimulation. Six males received additional recombinant follicle-stimulating hormone (FSH) supplementation 150-225 IU twice weekly.Results:After recombinant gonadotropin therapy, viable spermatozoa were retrieved from the ejaculate in two patients and by testicular sperm aspiration (TESA) in another two subjects. Singleton spermatozoon retrieved from testes were frozen by vitrification on Cell-Sleeper devices. Two live births were obtained after intracytoplasmic sperm injection with ejaculated spermatozoa and one live birth and an ongoing pregnancy using thawed spermatozoa from TESA.Conclusion:Our proof-of-concept study indicates that hormonal therapy with recombinant gonadotropins could be considered in infertile men with NOA as an alternative to sperm donation. Large-scale studies are needed to substantiate hormone stimulation therapy with recombinant gonadotropins in routine clinical practice for this severe form of male infertility.

Effect of the co-administration of HCG and GnRH agonist (dual trigger) versus standard HCG trigger on morphokinetic embryo parameters

Research questionDoes dual trigger (the co-administration of triptorelin 0.2 mg and recombinant human chorionic gonadotrophin (HCG) [Decapeptyl 0.2 mg + Ovitrelle 250 µg]) versus standard recombinant HCG (Ovitrelle 250 µg) affect embryo quality and morphokinetic parameters? DesignMorphokinetic parameters and embryo quality of embryos derived from the first gonadotrophin-releasing hormone (GnRH) antagonist IVF/intracytoplasmic sperm injection (ICSI) cycles triggered by dual trigger or standard HCG trigger in women ≤42 years. Outcome measures included time to pronucleus fading (tPNf), cleavage timings (t2–t8), synchrony of the second cycle (s2), duration of the second cycle (cc2) and known implantation data (KID) scoring for embryo quality. Multivariate linear and logistic regression analyses were performed for confounding factors. ResultsA total of 4859 embryos were analysed: 1803 embryos from 267 cycles in the dual trigger group and 3056 embryos from 463 cycles in the HCG trigger group. The groups were similar in patient and treatment characteristics apart from a higher maternal body mass index and lower maturation rate in the dual trigger group. Time to second polar body extrusion was shorter in the dual trigger group. Cleavage timings from zygote to an 8-cell embryo did not differ between the two groups. There was a higher percentage of embryos with an optimal cc2 duration in the HCG group. In multivariate logistic regression models, the trigger type was not a significant factor for cell cycle division parameters. ConclusionsOverall, there was no significant difference in the morphokinetic parameters or quality of embryos evaluated using a time-lapse monitoring system between embryos derived following dual trigger compared with HCG.

Does the HCG trigger dose used for IVF impact luteal progesterone concentrations? a randomized controlled trial

Research questionIs there an association between the ovulation trigger dose of human chorionic gonadotrophin (HCG) and endogenous progesterone production during the luteal phase? DesignThis randomized controlled four-arm study, at the Fertility Clinic, Odense University Hospital, Denmark, included women undergoing gonadotrophin-releasing hormone (GnRH) antagonist IVF treatment with ≤11 follicles ≥12 mm. Group 1–3 were triggered with 5000 IU, 6500 IU or 10,000 IU HCG, respectively, receiving 17α-hydroxyprogesterone caproate intramuscularly for luteal-phase support (LPS) to measure endogenous progesterone production. Group 4 received 6500 IU HCG trigger and vaginal progesterone. During the study, the 5000 IU and 10,000 IU HCG groups were switched from urinary to recombinant HCG, as urinary HCG was removed from market. Eight blood samples were drawn during the luteal phase. ResultsNinety-four participants completed the study. There was a significant positive association between the HCG trigger dose and the progesterone at 8 days (P < 0.001), 10 days (P < 0.001) and 14 days (P < 0.001) post-oocyte retrieval. Comparing the groups individually revealed a significant difference in progesterone concentration between low and high trigger doses at 4 days (P = 0.037) and 8 days (P = 0.007) post-oocyte retrieval and between all intervention groups at oocyte retrieval + 6 days: group 1 and 2 (P = 0.011), group 2 and 3 (P = 0.042) and group 1 and 3 (P < 0.001). Higher HCG trigger dose increased the progesterone from the individual follicle. ConclusionsIncreasing HCG trigger doses significantly increased endogenous progesterone concentration during the mid–late luteal phase.