hCG Priming in Women With Low Ovarian Reserve

Study Overview
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Brief Summary
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The aim of this trial is to examine the possible effects of hCG administration for eight weeks prior to IVF/ICSI in women with low ovarian reserve. Primary outcome is the proportion of the antral follicle count that reach the pre-ovulatory stage.

Detailed Description
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One of the fundamental goals in In Vitro Fertilisation (IVF) is obtaining a high number of good quality oocytes, in order to select and transfer embryos with the highest possible implantation potential thereby optimizing the chance of a pregnancy and ultimately a live birth. This is done by applying an individualized controlled ovarian stimulation (iCOS) protocol, primarily based on ovarian reserve markers like antral follicle count (AFC) and Anti-Müllerian hormone (AMH), when deciding the follicle stimulating hormone (FSH) stimulation dose. Certain patients, the so called poor ovarian responders' (PORs), pose a clinical challenge because they have a poor ovarian reserve and develop a limited number of pre-ovulatory follicles in respond to ovarian stimulation despite high FSH stimulation doses, thus experiencing reduced live birth rates. The aim of the present study is to examine the possible effects of long-term LH activity by the administration of hCG for eight weeks in between two identical IVF/ICSI cycles and compare cycle characteristics and outcome. The primary outcome is the follicular output rate (FORT) which reflects the proportion of antral follicles at the start of controlled ovarian stimulation that reaches the pre-ovulatory state. Secondary outcomes include amongst others AMH and antral follicle count at baseline (cd 2-3), number of pre-ovulatory follicles, oocytes retrieved, and embryos developed. We hypothesize that eight weeks of androgen priming by hCG increases the proportion of antral follicles that reaches the pre-ovulatory state during controlled ovarian stimulation for IVF/ICSI in women with poor ovarian reserve.

Official Title
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Eight Weeks of Androgen Priming by hCG Before IVF/ICSI in Women With Low Ovarian Reserve

Conditions
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Infertility, Female, Ovarian Reserve, In Vitro Fertilization

Intervention / Treatment
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* Drug: Ovitrelle


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Regular menstrual cycle (23-35 days) 1.-5. IVF/ICSI cycle at inclusion AMH < 6.29 pmol/L (Elecsys® AMH assay) Exclusion Criteria: Uterine malformations or hydrosalpinx Submucosal uterine myomas Uterine polyps Allergy to standard IVF/ICSI medication Endometriosis stage III-IV Severe comorbidity Preimplantation genetic testing Testicular sperm aspiration/extraction Tumors in the hypothalamus or pituitary gland Active thromboembolic disease

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Women will undergo two identical consecutive IVF/ICSI treatments: a Control cycle including blastocyst culture and freeze-all and a subsequent identical Study cycle, separated by eight weeks of androgen priming by daily hCG-injections. Both IVF/ICSI cycles are performed in the fixed GnRH-antagonist protocol using a daily dose of 300 IU rFSH initiated from cd 2-3 and the GnRH antagonist (Fyremadel 0.25 mg) from stimulation day 5-6.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: hCG priming<br>Control cycle: A standard IVF/ICSI cycle in the fixed GnRH-antagonist protocol using a daily dose of 300 IU rFSH initiated from cd 2-3 and the GnRH antagonist (Fyremadel 0.25 mg) from stimulation day 5-6 followed by blastocyst culture and a freeze-all strategy. Study cycle: hCG priming by Ovitrelle 260 IE once daily for 8 weeks followed by a standard IVF/ICSI cycle in the fixed GnRH-antagonist protocol using a daily dose of 300 IU rFSH initiated from cd 2-3 and the GnRH antagonist (Fyremadel 0.25 mg) from stimulation day 5-6 followed by a single blastocyst transfer at day 5. | Drug: Ovitrelle<br>* Ovitrelle 260 IE once daily for 8 weeks prior to IVF/ICSI<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Follicular output rate | Follicular Output Rate (FORT: pre-ovulatory follicle count (>16 mm) at hCG trigger day/antral follicle count at baseline (2-10 mm). | Through study completion, an average of 5 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Antral follicle count (≤10 mm) at baseline (cd 2-3) |  | Through study completion, an average of 5 months | 
| AMH at baseline (CD 2-3) |  | Through study completion, an average of 5 months | 
| Number of pre-ovulatory follicles >16 mm on trigger day |  | Through study completion, an average of 5 months | 
| Number of follicles >14 mm and >12 mm, >10 mm and ≤10 mm on hCG trigger day |  | Through study completion, an average of 5 months | 
| Number of oocytes retrieved |  | Through study completion, an average of 5 months | 
| Number of mature (MII) oocytes |  | Through study completion, an average of 5 months | 
| Number of fertilized eggs (2pn) |  | Through study completion, an average of 5 months | 
| Number of cleaved day 2 embryos |  | Through study completion, an average of 5 months | 
| Number of good quality day 2 embryos |  | Through study completion, an average of 5 months | 
| Number of top quality day 2 embryos |  | Through study completion, an average of 5 months | 
| Number of blastocysts (Gardner score 1-6) |  | Through study completion, an average of 5 months | 
| Number of good quality blastocysts day 5/6 |  | Through study completion, an average of 5 months | 
| Number of vitrified embryos/blastocysts |  | Through study completion, an average of 5 months | 
| Total number of transferred or vitrified blastocysts |  | Through study completion, an average of 5 months | 
| The number of cancelled cycles and the reasons for cancellation in the two groups |  | Through study completion, an average of 5 months | 
| Serum and follicular fluid hormonal levels (AMH, estradiol, progesterone, 17-OH-progesterone, hCG, LH, FSH, testosterone, androstenedione and Inhibin B |  | Through study completion, an average of 5 months | 
| Granulosa/cumulus cell FSH and LH receptor expression |  | 1 year | 
| Cumulus/corona gene expression analysis by quantitative PCR using three predictive genes (EFNB2, SASH1, CAMK1D). |  | 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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IVF, Poor ovarian reserve, Controlled ovarian stimulation, Ovarian stimulation, hCG priming