Hormone Evaluation in Artificial Reproductive Technology (HEART)

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.

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.

Study Overview

• Status: Completed
• Conditions: Female Infertility
• Intervention / Treatment: Drug: Follitropin alpha; Drug: Menotropin

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 810
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Poland
  • Poznań, Poland
    • Poznan University of Medical Sciences
• Sweden
  • Malmö, Sweden, 21428
    • Reproductive Medicine Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years to 36 years (Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Health Services Research
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Ovarian hyper stimulation syndrome	Association between overreaction to hormonal stimulation and genotype is analysed	Up to 6 months after treatment
Poor response	No or poor development of eggs in response to drug is analysed, genotype taken into account	Up to 6 months after treatment

Collaborators and Investigators

• Sponsor: Lund University
• Collaborators: European Commission
• Investigators: Principal Investigator: Yvonne Lundberg Giwercman, PhD, Lund University, Lund, Sweden

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2016
• Primary Completion (Actual): December 31, 2021
• Study Completion (Actual): October 2, 2024

Study Registration Dates

• First Submitted: October 23, 2018
• First Submitted That Met QC Criteria: November 7, 2018
• First Posted (Actual): November 9, 2018

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: March 14, 2025
• Last Verified: March 1, 2025

More Information

Terms related to this study

• Keywords: receptor; assisted reproduction; gonadotropin
• Additional Relevant MeSH Terms: Urogenital Diseases; Genital Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Genital Diseases, Female; Infertility; Infertility, Female; Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Reproductive Control Agents; Fertility Agents, Female; Fertility Agents; Follicle Stimulating Hormone; Menotropins
• Other Study ID Numbers: 2016_467

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No