Non-Obstructive Azoospermia and Intracytoplasmic Sperm Injection: Unveiling the Chances of Success and Possible Consequences for Offspring.

Non-obstructive azoospermia (NOA) is found in up to 15% of infertile men. While several causes for NOA have been identified, the exact etiology remains unknown in many patients. Advances in assisted reproductive technology, including intracytoplasmic sperm injection (ICSI) and testicular sperm retrieval, have provided hope for these patients. This review summarizes the chances of success with ICSI for NOA patients and examines preoperative factors and laboratory techniques associated with positive outcomes. Furthermore, we reviewed possible consequences for offspring by the use of ICSI with testicular sperm retrieved from NOA patients and the interventions that could potentially mitigate risks. Testicular sperm retrieved from NOA patients may exhibit increased chromosomal abnormalities, and although lower fertilization and pregnancy rates are reported in NOA patients compared to other forms of infertility, the available evidence does not suggest a significant increase in miscarriage rate, congenital malformation, or developmental delay in their offspring compared to the offspring of patients with less severe forms of infertility or the offspring of fertile men. However, due to limited data, NOA patients should receive specialized reproductive care and personalized management. Counseling of NOA patients is essential before initiating any fertility enhancement treatment not only to mitigate health risks associated with NOA but also to enhance the chances of successful outcomes and minimize possible risks to the offspring.

Midluteal serum estradiol levels are associated with live birth rates in hormone replacement therapy frozen embryo transfer cycles: a cohort study.

OBJECTIVE: To study whether midluteal serum estradiol (E2) levels are associated with the live birth rate in hormone replacement therapy frozen embryo transfer (HRT-FET) cycles in patients with optimal midluteal serum progesterone (P4) levels. DESIGN: Observational prospective cohort study. SETTING: Public fertility clinic. PATIENTS: A total of 412 women had an HRT-FET cycle single blastocyst transfer from January 2020 to November 2022. INTERVENTION: The HRT-FET cycle priming regimen included oral E2 (6mg/24 h) administered in the evening, followed by vaginal P4 (400mg/12 h). Serum E2 and P4 levels were measured using a standardized method, 2-4 hours after the latest P4 administration and 9-14 hours after E4 administration on the day of blastocyst transfer, day 6 of P4 administration. Patients with serum P4 levels (<11 ng/mL [35 nmol/L]) on the day of transfer received additional rectal P4 (400mg/12 h). No additional E2 dose was administered. MAIN OUTCOME MEASURES: The primary outcome was the live birth rate (LBR) in relation to E2 levels at blastocyst transfer day. RESULTS: The optimal serum E2 levels correlating with ongoing pregnancy were ≥292 pg/mL and <409 pg/mL (≥1,070 pmol/L and <1,500 pmol/L). The LBR was 59% (60/102) when E2 levels were within this range, whereas a significantly lower LBR of 39% (101/260) was seen in patients when E2 levels were <292 pg/mL (<1,070 pmol/L) and of 28% (14/50) when E2 levels were ≥409 pg/mL (≥1,500 pg/mL). In a logistic regression analysis, adjusting for serum P4 level ≥11 ng/mL or <11 ng/mL (≥35 nmol or <35 nmol/L) on the day of transfer, body mass index, age at oocyte retrieval, day 5 or 6 vitrified blastocysts, and blastocyst score, the adjusted risk difference of live birth was -0.21 (-0.32; -0.10) when the E2 level was <292 pg/mL (<1,070 pmol/L) and -0.31 (-0.45; -0.18) when the E2 level was ≥409 pg/mL (≥1,500 pmol/L) compared with E2 levels ≥292 pg/mL and <409 pg/mL (≥1,070 and <1,500 pmol/L). Importantly, only 25% of patents had optimal levels. CONCLUSION: The study shows a significant association between serum E2 levels and reproductive outcomes in an HRT-FET cohort in which optimal serum P4 levels were secured. Midluteal serum E2 levels are associated with the LBR in HRT-FET cycles, and E2 levels should neither be too high nor too low. CLINICAL TRIAL REGISTRATION NUMBER: EudraCT No.: 2019-001539-29.

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

ABSTRACT Purpose: 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.

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

PURPOSE: 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.

The combined effect of lifestyle intervention and antioxidant therapy on sperm DNA fragmentation and seminal oxidative stress in IVF patients: a pilot study

ABSTRACT Purpose: Sperm DNA fragmentation (SDF) and seminal oxidative stress are emerging measurable factors in male factor infertility, which interventions could potentially reduce. We evaluated (i) the impact of lifestyle changes combined with oral antioxidant intake on sperm DNA fragmentation index (DFI) and static oxidation-reduction potential (sORP), and (ii) the correlation between DFI and sORP. Materials and Methods: We conducted a prospective study involving 93 infertile males with a history of failed IVF/ICSI. Ten healthy male volunteers served as controls. Semen analysis was carried out according to 2010 WHO manual, whereas seminal sORP was measured using the MiOXSYS platform. SDF was assessed by sperm chromatin structure assay. Participants with DFI >15% underwent a three-month lifestyle intervention program, primarily based on diet and exercise, combined with oral antioxidant therapy using multivitamins, coenzyme Q10, omega-3, and oligo-elements. We assessed changes in semen parameters, DFI, and sORP, and compared DFI results to those of volunteers obtained two weeks apart. Spearman rank correlation tests were computed for sORP and DFI results. Results: Thirty-eight (40.8%) patients had DFI >15%, of whom 31 participated in the intervention program. A significant decrease in median DFI from 25.8% to 18.0% was seen after the intervention (P <0.0001). The mean DFI decrease was 7.2% (95% CI: 4.8-9.5%; P <0.0001), whereas it was 0.42% (95%CI; -4.8 to 5.6%) in volunteers (P <0.00001). No differences were observed in sperm parameters and sORP. Based on paired sORP and DFI data from 86 patients, no correlation was observed between sORP and DFI values (rho=0.03). Conclusion: A 3-month lifestyle intervention program combined with antioxidant therapy reduced DFI in infertile men with elevated SDF and a history of failed IVF/ICSI. A personalized lifestyle and antioxidant intervention could improve fertility of subfertile couples through a reduction in DFI, albeit controlled trials evaluating reproductive outcomes are needed before firm conclusions can be made. Trial registration number and date: clinicaltrials.gov NCT03898752, April 2, 2019.

The combined effect of lifestyle intervention and antioxidant therapy on sperm DNA fragmentation and seminal oxidative stress in IVF patients: a pilot study.

PURPOSE: Sperm DNA fragmentation (SDF) and seminal oxidative stress are emerging measurable factors in male factor infertility, which interventions could potentially reduce. We evaluated (i) the impact of lifestyle changes combined with oral antioxidant intake on sperm DNA fragmentation index (DFI) and static oxidation-reduction potential (sORP), and (ii) the correlation between DFI and sORP. MATERIALS AND METHODS: We conducted a prospective study involving 93 infertile males with a history of failed IVF/ICSI. Ten healthy male volunteers served as controls. Semen analysis was carried out according to 2010 WHO manual, whereas seminal sORP was measured using the MiOXSYS platform. SDF was assessed by sperm chromatin structure assay. Participants with DFI >15% underwent a three-month lifestyle intervention program, primarily based on diet and exercise, combined with oral antioxidant therapy using multivitamins, coenzyme Q10, omega-3, and oligo-elements. We assessed changes in semen parameters, DFI, and sORP, and compared DFI results to those of volunteers obtained two weeks apart. Spearman rank correlation tests were computed for sORP and DFI results. RESULTS: Thirty-eight (40.8%) patients had DFI >15%, of whom 31 participated in the intervention program. A significant decrease in median DFI from 25.8% to 18.0% was seen after the intervention (P <0.0001). The mean DFI decrease was 7.2% (95% CI: 4.8-9.5%; P <0.0001), whereas it was 0.42% (95%CI; -4.8 to 5.6%) in volunteers (P <0.00001). No differences were observed in sperm parameters and sORP. Based on paired sORP and DFI data from 86 patients, no correlation was observed between sORP and DFI values (rho=0.03). CONCLUSION: A 3-month lifestyle intervention program combined with antioxidant therapy reduced DFI in infertile men with elevated SDF and a history of failed IVF/ICSI. A personalized lifestyle and antioxidant intervention could improve fertility of subfertile couples through a reduction in DFI, albeit controlled trials evaluating reproductive outcomes are needed before firm conclusions can be made. Trial registration number and date: clinicaltrials.gov NCT03898752, April 2, 2019.

GnRH agonist supplementation in hormone replacement therapy-frozen embryo transfer cycles: a randomized controlled trial.

RESEARCH QUESTION: Will two boluses of gonadotrophin-releasing hormone agonist (GnRHa) during hormone replacement therapy-frozen embryo transfer (HRT-FET) cycles reduce the total pregnancy loss rate? DESIGN: Randomized controlled trial including a total of 287 HRT-FET cycles performed between 2013 and 2019. After randomization participants allocated to the GnRHa group (n = 144) underwent a standard HRT protocol, supplemented with a total of two boluses of triptorelin 0.1 mg; one bolus 2 days before starting vaginal progesterone and one bolus on the 7th day of progesterone. The control group (n = 143) underwent a standard HRT-FET protocol only. RESULTS: The intention-to-treat analysis showed no significant difference in total pregnancy loss between the GnRHa group and the control group (21% versus 33%; relative risk [RR] 0.63, 95% confidence interval [CI] 0.35-1.11), nor was the biochemical pregnancy loss per positive human chorionic gonadotrophin (HCG) significantly lower in the GnRHa group (12%, 8/67) compared with the control group (25%, 18/72) (RR 0.48, 95% CI 0.22-1.02). Participants with a live birth had a significantly higher mean progesterone concentration compared with participants without a live birth (25.0 ± 12.2 versus 23.8 ± 8.9 nmol/l; P = 0.001). Furthermore, a trend for a higher live birth rate (LBR) correlated with the highest oestradiol quartile concentration (oestradiol >0.957 nmol/l). CONCLUSIONS: Although a difference of 14% in biochemical loss and 12% in total pregnancy loss in favour of GnRHa supplementation was seen this did not reach statistical difference. Luteal progesterone and oestradiol concentrations correlate with LBR in the HRT-FET cycle, emphasizing the importance of luteal serum progesterone and oestradiol monitoring.

The exogenous progesterone-free luteal phase: two pilot randomized controlled trials in IVF patients.

RESEARCH QUESTION: Is the reproductive outcome similar after gonadotrophin-releasing hormone agonist (GnRHa) trigger followed by luteal human chorionic gonadotrophin (HCG) boluses compared with HCG trigger and a standard luteal phase support (LPS)? DESIGN: Two open-label pilot randomized controlled trials (RCT) with 250 patients from 2014 to 2019, with a primary outcome of ongoing pregnancy per embryo transfer. Patients with ≤13 follicles on the trigger day were randomized (RCT 1) to: Group A (n = 65): GnRHa trigger followed by a bolus of 1500 IU HCG s.c. on the oocyte retrieval day (ORD) and 1000 IU HCG s.c. 4 days later, and no vaginal LPS; or Group B (n = 65): 6500 IU HCG trigger, followed by a standard vaginal progesterone LPS. Patients with 14-25 follicles on the trigger day were randomized (RCT 2) to Group C (n = 60): GnRHa trigger followed by 1000 IU HCG s.c. on ORD and 500 IU HCG s.c. 4 days later, and no vaginal LPS; or Group D (n = 60): 6500 IU HCG trigger and a standard vaginal LPS. RESULTS: In RCT 1, the ongoing pregnancy rate was 44% (22/50) in the GnRHa group versus 46% (25/54) in the HCG trigger group (RR 0.95, 95% CI 0.62-1.45). No ovarian hyperstimulation syndrome (OHSS) was seen in Groups A or B. In RCT 2, the ongoing pregnancy rate was 51% (25/49) in the GnRHa group versus 60% (31/52) in the HCG trigger group (RR 0.86, 95% CI 0.60-1.22). The OHSS rates were 3.3% and 6.7%, respectively. CONCLUSIONS: Although a larger-scale study is needed before standard clinical implementation, the present study supports that the exogenous progesterone-free LPS is efficacious, simple and patient-friendly.

SARS-CoV-2 pandemic and repercussions for male infertility patients: A proposal for the individualized provision of andrological services.

The prolonged lockdown of health facilities providing non-urgent gamete cryopreservation-as currently recommended by many reproductive medicine entities and regulatory authorities due to the SARS-CoV-2 pandemic will be detrimental for subgroups of male infertility patients. We believe the existing recommendations should be promptly modified and propose that the same permissive approach for sperm banking granted for men with cancer is expanded to other groups of vulnerable patients. These groups include infertility patients (eg, azoospermic and cryptozoospermic) undergoing medical or surgical treatment to improve sperm quantity and quality, as well as males of reproductive age affected by inflammatory and systemic auto-immune diseases who are about to start treatment with gonadotoxic drugs or who are under remission. In both scenarios, the "fertility window" may be transitory; postponing diagnostic semen analysis and sperm banking in these men could compromise the prospects of biological parenthood. Moreover, we provide recommendations on how to continue the provision of andrological services in a considered manner and a safe environment. Our opinion is timely and relevant given the fact that fertility services are currently rated as of low priority in most countries.

Dual stimulation using corifollitropin alfa in 54 Bologna criteria poor ovarian responders - a case series.

RESEARCH QUESTION: What are the reproductive outcomes of Bologna criteria poor responders undergoing dual stimulation (DuoStim) and subsequent cryopreserved embryo transfer? DESIGN: Case series of patients treated during the period August 2015 to March 2018 in a public fertility clinic. The study included 54 Bologna criteria poor responder IVF patients younger than 42 years receiving a follicular stimulation (DuoStim 1) followed by a luteal phase stimulation (DuoStim 2) within the same cycle, both stimulations being performed with corifollitropin alfa followed by a subsequent cryopreserved embryo transfer cycle. The primary endpoint was the number of oocytes retrieved in DuoStim 1 compared with DuoStim 2. The secondary endpoint was ongoing pregnancy rate (OPR) at 12 weeks of gestation. RESULTS: The mean number of oocytes retrieved in DuoStim 1 and DuoStim 2 was 2.4 ± 2.1 versus 3.7 ± 2.6, respectively; thus, a total of 1.2 (95% CI, 0.46-1.96) more oocytes was retrieved in DuoStim 2 compared with DuoStim 1 (P = 0.002). The OPR at 12 weeks was 20% (11/54) in this poor ovarian response population with a mean age of 36.7 years. CONCLUSIONS: Luteal phase stimulation results in more oocytes in poor responders compared with follicular phase stimulation. DuoStim, using corifollitropin alfa followed by individualized FSH dosing, appears to be an alternative to conventional follicular phase stimulation, decreasing the risk of cycle cancellation.

Vaginal Microbiota and In Vitro Fertilization Outcomes: Development of a Simple Diagnostic Tool to Predict Patients at Risk of a Poor Reproductive Outcome.

BACKGROUND: Female reproductive tract microbiota may affect human reproduction. The current study considered whether a more detailed characterization of the vaginal microbiota could improve prediction of risk of poor reproductive outcome in patients undergoing in vitro fertilization (IVF). METHODS: Vaginal samples from 120 patients undergoing IVF were sequenced using the V4 region of the 16S ribosomal RNA gene with clustering of Gardnerella vaginalis genomic clades. Abnormal vaginal microbiota was defined by microscopy and quantitative polymerase chain reaction (qPCR) for G. vaginalis and/or Atopobium vaginae above a threshold. RESULTS: Three major community state types with abundance of Lactobacillus crispatus, Lactobacillus iners, and a diverse community type were identified, including 2 subtypes, characterized by a high abundance of L. crispatus and L. iners, respectively, but in combination with common diversity type operational taxonomic units. No significant association between community state type and the reproductive outcome could be demonstrated; however, abnormal vaginal microbiota by qPCR and a grouping based on high Shannon diversity index predicted the reproductive outcome equally well. CONCLUSIONS: The predictive value of 16S ribosomal RNA gene sequencing was not superior to the simpler and less expensive qPCR diagnostic approach in predicting the risk of a poor reproductive outcome in patients undergoing IVF. CLINICAL TRIALS REGISTRATION: NCT02042352.

Progesterone levels on pregnancy test day after hormone replacement therapy-cryopreserved embryo transfer cycles and related reproductive outcomes.

RESEARCH QUESTION: Do serum progesterone levels determine ongoing pregnancy rates (OPR) in hormone replacement therapy frozen-thawed embryo transfer (HRT-FET) cycles? DESIGN: A cohort study of 244 HRT-FET cycles from a Danish public fertility centre. Data from patients undergoing HRT-FET from January 2016 to December 2017 were extracted from a clinical database. All patients had transfer in HRT cycles of autologous embryos frozen on day 5 or 6. Endometrial preparation was performed using 6 mg oestradiol valerate daily from the second day of the cycle followed by vaginal micronized progesterone (90 mg/8 h). All patients had serum progesterone measurement during the artificial luteal phase. RESULTS: The optimal cut-off for ongoing pregnancy was 35 nmol/l based on sensitivity analysis of different progesterone levels as a factor variable and its association with ongoing pregnancy. No significant differences regarding number of embryos transferred, embryo quality, age, body mass index (BMI) or smoking were found in the two groups of progesterone < 35 nmol/l and ≥ 35 nmol/l, respectively. A total of 51% of patients had a serum progesterone < 35 nmol/l. The range of all measurements was 0.3 to 110 nmol/l. The unadjusted OPR was significantly lower in the < 35 nmol/l group compared with the ≥ 35 nmol/l group (38% versus 51%;P = 0.04). A logistic regression analysis, adjusting for smoking, age, BMI, number of embryos transferred and blastocyst age showed a significant decrease in OPR when progesterone was < 35 nmol/l of 44% (95% confidence interval [CI] 35-54%) compared with ≥ 35 nmol/l of 58% (95% CI 48-68%), risk difference of 14% (95% CI 2-26%,P = 0.02). CONCLUSIONS: Serum progesterone levels < 35 nmol/l decrease the chance of OPR in HRT-FET cycles.

Treatment of Abnormal Vaginal Microbiota before Frozen Embryo Transfer: Case-Report and Minireview to Discuss the Longitudinal Treatment Efficacy of Oral Clindamycin.

Abnormal vaginal microbiota (AVM) or bacterial vaginosis (BV) might negatively impact reproductive outcomes of in vitro fertilization (IVF). However, before randomized controlled trials are initiated to investigate cause and effect, it is necessary to establish the optimal treatment for AVM. Metronidazole seems ineffective to treat the biofilm in AVM; thus, clindamycin could be suggested as a relevant antibiotic agent for future intervention based studies. In the present case report, we present the first longitudinal follow-up of the vaginal microbiota with molecular methods during and after oral clindamycin treatment. Furthermore, we review the recent literature with the aim to discuss the optimal AVM treatment in a fertility setting. The patient was 40 years old suffering from unexplained secondary infertility. Prior to the present transfer cycle, she had had two failed IVF cycles. The tentative explanation of failed treatment was age-related aneuploidy. However, the patient asked for AVM diagnosis and she was subsequently diagnosed and treated successfully. Unfortunately, the patient did not achieve pregnancy after clindamycin treatment and two subsequent frozen embryo transfer cycles. Taken together, we report an excellent AVM treatment efficacy both short-term and long-term following oral clindamycin treatment. We discuss the potential impact on the vaginal microbiota of co-treatment with estrogen patches in the stimulated frozen embryo transfer cycle. Furthermore, we discuss future aspects of AVM treatment such as the potential impact of estrogen and live biotherapeutic products to positively modulate the microbiota of the reproductive tract.

Bio-equivalent doses of recombinant HCG and recombinant LH during ovarian stimulation result in similar oestradiol output: a randomized controlled study.

In nature, HCG is secreted by the implanting embryo from peri-implantation and onwards. In contrast, LH is mandatory for steroidogenesis and follicular development during the follicular phase, working in synergy with FSH. Moreover, LH is mandatory for the function of the corpus luteum. Although LH and HCG bind to the same receptor, significant molecular, structural and functional differences exist, inducing differences in bioactivity. This randomized controlled study compared the effect of recombinant FSH stimulation combined with daily either micro-dose recombinant HCG or recombinant LH supplementation in a 1:1 bioactivity ratio from day 1 of stimulation in a long gonadotrophin releasing hormone agonist down regulation protocol. A total of 100 patients from a public clinic completed the study. The primary end-point was the oestradiol level on the day of ovulation trigger and the median oestradiol level in the HCG supplemented group was 8662 pmol/l versus 9203 pmol/l in the recombinant LH supplemented group; therefore, no significant difference was found. Moreover, no differences were observed in the number of oocytes retrieved or in the live birth rate. We conclude that recombinant HCG and recombinant LH are equally effective in boosting oestradiol synthesis during ovarian stimulation when used in a 1:1 bioactivity ratio.

Pregnancy and birth after intracytoplasmic sperm injection with normal testicular spermatozoa in a patient with azoospermia and tail stump epididymal sperm

Main findings: An intriguing yet perplexing case report of a successful pregnancy and live birth with intracytoplasmic sperm injection using normal testicular sperm, after the finding of azoospermia in the semen analysis and discovering only tail stump abnormal sperm in the epididymis. Case hypothesis: A tail stump sperm defect of genetic origin was suspected. However, after obtaining normal testicular sperm we concluded that obstructive azoospermia, either idiopathic or secondary to multiple minor genital trauma was the plausible scenario. This has rendered the search of previous reports on a similar condition, but none was found. However, it has raised scientific thoughts for future research. Promising future implications: The importance of reporting this case is to alert urologists performing sperm retrieval that healthy and morphologically normal sperm may be found in the testis of azoospermic men with 100% tail stump epididymal sperm. Retrieval of normal testicular sperm obviates the need of a more complex investigation, including sperm electron microscopy. It also offers the possibility of utilizing such gametes for sperm injections rather than abnormal tail stump sperm that may be associated with a poor reproductive outcome.

Daily low-dose hCG stimulation during the luteal phase combined with GnRHa triggered IVF cycles without exogenous progesterone: a proof of concept trial.

STUDY QUESTION: Can the luteal phase support be improved in terms of efficacy, hormonal profiles and convenience as compared with today's standard care? SUMMARY ANSWER: Daily low-dose rhCG supplementation in GnRHa triggered IVF cycles can replace the traditional used luteal phase support with exogenous progesterone. WHAT IS KNOWN ALREADY: A bolus of hCG for final maturation of follicles in connection with COS may induce the risk of OHSS and the luteal phase progesterone levels rise very abruptly in the early luteal phase. STUDY DESIGN, SIZE, DURATION: This is a proof-of-concept study conducted as a three arm RCT with a total of 93 patients. First patient enrolled in January 2012 and the study finished in January 2014. PARTICIPANTS/MATERIALS, SETTING, METHODS: Normal responder women undergoing IVF/ICSI treatment in a university hospital. One arm served as control, where women followed a standard antagonist protocol. Two study arms were included both having 125 IU hCG daily for luteal phase support without exogenous progesterone after using a GnRHa trigger for ovulation induction. In both study arms exogenous FSH was stopped on stimulation day 6 and replaced by exogenous hCG that was initiated on either stimulation day 2 or day 6. Blood samples were obtained on the day of ovulation induction, on the day of oocyte pickup (OPU) and day OPU + 7. MAIN RESULTS AND THE ROLE OF CHANCE: The mean serum levels of hCG did not exceeded the normal physiological range of LH activity in any samples. Mid-luteal progesterone levels were significantly higher in the two study groups receiving daily low-dose hCG for luteal phase support as compared with the control group (control group: 177 ± 27 nmol/l; study group 1: 334 ± 42 nmol/l; study group 2: 277 ± 27 nmol/l; (mean ± SEM). No differences in reproductive outcome were seen between groups. LIMITATIONS, REASONS FOR CAUTION: The number of patients included is limited and conclusions need to be verified in a larger RCT. WIDER IMPLICATIONS OF THE FINDINGS: Endogenous production of progesterone may become more attractive as the luteal phase support with levels of LH-like activity only in the physiological range and may, from the patients' point of view, replace inconvenient exogenous progesterone preparation. Further hCG may reduce the cost of stimulation and may collectively be used for stimulation of the follicular phase, ovulation induction and for luteal phase support. STUDY FUNDING/COMPETING INTERESTS: An unrestricted grant from ARTS Biologics made this study possible. None of the authors has any competing interests to declare. TRIAL REGISTRATION NUMBER: ClinicalTrial.gov number: NCT01504139. TRIAL REGISTRATION DATE: 28 December 2011.