The Angiotensin-Melatonin Axis in Poor and Hyper Responders for IVF Treatment

July 8, 2022 updated by: Rym Ghimouz, Fatima College of Health Sciences
According the World Health Organization (WHO), infertility is a disease of the male or female reproductive system defined by the failure to achieve a pregnancy after 12 months or more of regular unprotected sexual intercourse. In-vitro-fertilization (IVF) is considered to be a successful tool to overcome infertility. However, the current methods used to assess the ovarian reserve and to develop an optimal individualized controlled ovarian hyperstimulation (COH) protocol have shown some limitations. Growing evidence indicates that altered renal renin-angiotensin system (RAS) and/or melatonin are linked to infertility. Aims and Objectives: The current 2 years duration study aims first to investigate the demographic and clinical profiles of patients undergoing IVF in the UAE. In the second phase of the study, we hypothesis that an altered angiotensin-melatonin axis may be considered as an unfavorable prognosis factor in poor and hyper responders undergoing IVF treatment. This hypothesis will be assessed using an observational, longitudinal, prospective clinical study to determine whether the urinary angiotensinogen and/or melatonin deficiency might be present in poor and hyper responders undergoing IVF treatment. Thus, negatively impacting the clinical pregnancy rate. Methodology: various patient's data will be collected using a questionnaire and the levels of angiotensinogen and melatonin in patient's urine will be measured using ELISA test prior to, during and after the IVF treatment. To determine whether the angiotensinogen-melatonin axis disruption affects the IVF treatment outcome, we will analyze the following parameters: the AMH, Antral Follicular Count (AFC), day 2-4 FSH levels, the stimulation cycle in regards to number of stimulation days and amount of gonadotropins used for stimulation, number of oocytes retrieved and number of mature oocytes, quality and embryo's ploidy, number of available euploid embryos and the clinical pregnancy rate after frozen embryo transfer.

Study Overview

Status

Not yet recruiting

Conditions

Detailed Description

Infertility affects approximately 1 in every 4 couples and the WHO (World Health Organization) has defined infertility as a "disease" (World Health Organization (WHO). International Classification of Diseases, 11th Revision (ICD-11) Geneva: WHO 2018.). Rates of infertility are expected to increase in the future as many couples tend to postpone family planning due to various reasons (Mills et al., 2011). Assisted Reproductive Techniques (ART), with In-vitro-fertilization (IVF) being a part of the treatment options, are a successful tool to overcome infertility (Franasiak & Scott, 2014). However, more research to thwart the global burden of infertility is required. This is possible if the underlying causes of infertility can be identified, and personalized therapy implemented (Sun et al., 2019).

Poor and hyper responders are a diverse group of IVF patients, with specific needs. Their management can help in increasing the clinical pregnancy rates. Identifying and understanding how the endocrine variants are linked to the success of IVF responsiveness may lead to a better treatment strategy aimed at achieving successful live births.

Growing evidence indicates that altered renal renin-angiotensin system (RAS) and melatonin are linked to infertility, PCOS and endometriosis.

According to the literature, hyperandrogenemia in an experimental rat model of PCOS has been associated with an upregulation of the intrarenal RAS (Torres Fernandez et al. 2019). When compared to the eutopic endometrium in the proliferative phase, patients with endometriotic cysts had a significant increase in the expression of angiotensin type AT1 and AT2 receptors. This suggests that RAS may be involved in the pathophysiology of endometriosis (Nakao et al. 2017; Nakajima et al. 2018). In addition, alterations in the expression of Angiotensin-converting enzyme, ACE-1, ACE-2, and ACE-3 might be one of the most important mechanisms underlying both female and male infertility (Chen, Bi, Su, Chappell, & Rose, 2016; Pan, Zhan, Le, Zheng, & Jin, 2013).

On the other hand, the levels of melatonin, a powerful antioxidant and an effective free radical scavenger that protects ovarian follicles during follicular maturation are increasing in preovulatory follicular fluid and seem to have an important role in ovulation (Tamura et al., 2012). Similarly, melatonin requirements appear to increase during pregnancy (Voiculescu, Zygouropoulos, Zahiu, & Zagrean, 2014). Melatonin levels are found to be lower in patients with PCOS (Mojaverrostami et al. 2019). And several studies suggest a potential link between melatonin and endometriosis (Mosher et al. 2019; Anderson 2019), leading to the use of melatonin as an adjuvant in the treatment of endometriosis (Mosher et al. 2019; Yesildaglar et al. 2016).

Clinical hypothesis:

This observational, longitudinal, prospective clinical study will investigate the IVF population demographic and clinical profile in the UAE. It will also test the hypothesis whether an altered angiotensin-melatonin axis may be considered an unfavorable prognosis factor in poor responders with or without endometriosis and hyper (PCOS) responders undergoing IVF treatment. Thus, negatively impacting the clinical pregnancy rate.

Study Type

Observational

Enrollment (Anticipated)

200

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 45 years (Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

Female

Sampling Method

Probability Sample

Study Population

From the ART Fertility Clinic, Abu Dhabi, UAE, our collaborator in the project, we are planning to enroll (following the selection criteria detailed below) for a duration of 18 months, IVF female patients aged between 18 and 45 years old and who volunteer to participate in the study. Participants in the study have to sign a participant Information sheet and consent form specific to the urine testing before their enrollment in the study. A questionnaire will be filled out with the different demographics and a summary of the IVF protocol details.

Description

Inclusion Criteria:

depending on the ART Fertility Clinic patients, we are intending to include:

  1. Women diagnosed with infertility (when pregnancy is not achieved after 1 year of having regular sexual intercourse without birth control for those under 35 years of age or if pregnancy is not achieved after 6 months of trying to conceive naturally for those older than 35 years of age). Further on, women with proven tubal factor infertility or couples with infertility as a result of a male factor, without the previously mentioned time of not achieving a pregnancy.
  2. Women undergoing or in the way to undergo IVF and classified as poor responders according to the four groups of the POSEIDON criteria (Conforti et al., 2019), including patients with a previous oral contraceptive intake.
  3. Women diagnosed with PCOS based on the Rotterdam criteria (Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group, 2004.
  4. Women diagnosed with endometriosis confirmed by Laparoscopy or visible endometrioma without being diagnosed by laparoscopy (If possible to be enrolled in the research).
  5. Women planned to undergo IVF treatment and categorized as expected normal responders) (Ozkan, 2019).
  6. Patients under thyroid medication.

Exclusion Criteria:

  1. Presence or history of endocrine abnormalities (at the exception of patients who are under thyroid medication).
  2. Abnormal outcome of blood biochemistry or hematology.
  3. Obese patients with BMI > 40.
  4. Couples for whom the male partner has to undergo surgical sperm retrieval.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Observational Models: Cohort
  • Time Perspectives: Prospective

Cohorts and Interventions

Group / Cohort
Poor IVF Treatment Responders
Hyper IVF Treatment Responders
Normal responders/ Control group

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Differences on urine levels of angiotensinogen-melatonin-creatinine ratio between two groups: one with AMH < 1.1 ng/ml against other with AMH > 6.25 ng/ml.
Time Frame: 18 months
Urinary excretion of angiotensinogen will be analyzed by sandwich-ELISA assay. Urinary melatonin excreted overnight will be determined through the 6-sulfatoxymelatonin molecule. This is a metabolite released in the urine that correlates directly with the melatonin produced, being a noninvasive method of dosing the said molecule. The urinary dosage of 6-sulfatoximelatonin will be performed by the ELISA technique according to the manufacturer's recommendations (IBL International Germany). All molecules will be quantitated using ELISA according to supplier's specifications.
18 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Fatima College of Health Sciences

Collaborators

ART Fertility Clinics LLC

Investigators

  • Principal Investigator: Rym Ghimouz, PhD, Fatima College of Health Sciences
  • Principal Investigator: Barbara Lawrenz, PhD, ART Fertility Clinics
  • Principal Investigator: Luciana Campos, PhD, Universidade Anhembi Morumbi

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Anticipated)

September 1, 2022

Primary Completion (Anticipated)

August 31, 2024

Study Completion (Anticipated)

August 31, 2024

Study Registration Dates

First Submitted

March 17, 2022

First Submitted That Met QC Criteria

March 17, 2022

First Posted (Actual)

March 28, 2022

Study Record Updates

Last Update Posted (Actual)

July 12, 2022

Last Update Submitted That Met QC Criteria

July 8, 2022

Last Verified

July 1, 2022

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • FCEC-1-21-22-GRD-1-SF
  • REFA073 (Other Identifier: ART Fertility Clinic Middle East Ethical Approval)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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