Hormone Evaluation in Artificial Reproductive Technology

Study Overview
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Brief Summary
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The aim is to be able to predict the hormonal response according to gonadotropin receptor genotype and hormone type used for treatment of women undergoing in vitro fertilization or egg donation. Outcome will be measured as pregnancy success, live born babies and unwanted side effects.

Detailed Description
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Women undergoing in vitro fertilization receive high doses of the gonadotropins follicle stimulating hormone (FSH) and human chorionic gonadotropin (hCG), which is acting as luteinizing hormone (LH) for stimulation of the ovaries in order to obtain a high number of eggs. There are however marked individual differences in the hormonal response, ranging from lack of increased egg maturation to hyper stimulation. The hypothesis is that genetic variants in the gonadotropin receptors (LH and FSH receptors), are influencing the outcome. This assumption is supported by a recent study on more than 600 women undergoing in vitro fertilization, demonstrating that whereas only 10% of women with asparagine in both genes (FSHR N680S and LHR N312S) became pregnant, 40% of those with serine did (Lindgren I et al. Hum Repr 2016; 3:672-83). Most (90%) of the women were treated with rFSH (recombinant). However, of the 10% asparagine carriers who actually became pregnant, most if not all, were treated with menotropin - a urine derivated compound (Menopur, Ferring), which contains both LH and FSH. This finding was not stressed in the manuscript as it could have been due to chance because of the small number of women treated with menotropin. The objective is therefore to perform a prospective randomized study regarding efficacy of treatment in the first and second in vitro fertilization trial with rFSH and menotropin, respectively, genotype taken into account. In total 890 women, 445 in Poznan, Poland and 445 in Malmö, Sweden, with unexplained infertility or a male or tubal factor indication for treatment will be invited to participate in the study. At first appointment, information is provided and informed consent retrieved. Two blood samples are drawn and stored at -20°C; one for subsequent genotyping and one for anti mullerian hormone measurement. The succeeding treatment is according to normal procedures at respective clinic.

Official Title
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Prospective Randomised Clinical Study on Pharmacogenetics of Gonadotropin Receptors in Relation to Pregnancy and Life Birth Rate as Well as Unwanted Side Effects Such as Ovarian Hyper Stimulation Syndrome During Assisted Reproduction.

Conditions
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Female Infertility

Intervention / Treatment
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* Drug: Follitropin alpha
* Drug: Menotropin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Normal ovulatory cycles 26-32 days First and second IVF treatment Indication for IVF is male factor, tubal factor or unexplained infertility Medical indication for IVF; >12 months unprotected intercourse Exclusion Criteria: Anti Müllerian Hormone <5pmol or cycle day 2-3 FSH >12 Endometriosis polycystic ovarian syndrome pre ovarian failure smoking male age more than 56.

Ages Eligible for Study
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Minimum Age: 25 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: Health Services Research
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Women undergoing in vitro fertilization are randomized to either menotropin (urin derivate) or recombinant follicle stimulating hormone. Inclusion criteria are: younger than 40 years of age more than 12 months of unprotected intercourse normal ovulatory cycles 26-32 days first or second IVF treatment indication for IVF is male factor tubal factor or unexplained infertility. Exclusion criteria are: Anti müllerian hormone less than 5pmol or FSH more than 12 cycle day 2-3 Endometriosis polycystic ovarian syndrome pre ovarian failure smoking male age more than 56. The succeeding treatment is according to normal procedures at respective clinic. End points are: total hormonal dosage, number of retrieved oocytes, fertilization rate, rate of blastocyst transfer, pregnancy rate, live birth rate. Adverse effects e.g overstimulation is recorded.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Follitropin alpha<br>Follitropin alpha (GONAL-f, Merck-Serono, Darmstadt, Germany), injections, dosage varying 1500-2500 IU, duration 2-5 days. | Drug: Follitropin alpha<br>* The objective is to measure the effect of the drug according to gonadotropin receptor genotype.<br>* Other names: Urofollitropin;Drug: Menotropin<br>* The objective is to measure the effect of the drug according to gonadotropin receptor genotype.<br>* Other names: Menopur;|
| Active Comparator: Menotropin<br>Menotropin (Menopur, Ferring GmbH, Kiel, Germany), injections, dosage varying 1500-2500 IU, duration 2-5 days. | Drug: Follitropin alpha<br>* The objective is to measure the effect of the drug according to gonadotropin receptor genotype.<br>* Other names: Urofollitropin;Drug: Menotropin<br>* The objective is to measure the effect of the drug according to gonadotropin receptor genotype.<br>* Other names: Menopur;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pregnancy | Association between pregnancy rate and genotype is evaluated | up to 12 months after treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of oocytes | Number of eggs developed in response to drug according to genotype is measured | up to 6 months after treatment | 
| live birth | Live birth rate according to genotype is analyzed | up to 12 months after treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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gonadotropin, receptor, assisted reproduction