Second Step Protocol in Poor Ovarian Responder (POR) (POR)

March 30, 2018 updated by: Antonia Iacovelli, Università degli Studi 'G. d'Annunzio' Chieti e Pescara

Repeated Luteal Phase Ovarian Stimulation (Second Step Protocol) in Poor Responder Patients

Reduced ovarian reserve and the consequent poor ovarian response are very recurent in infertile patients, indeed a percentage of 10%-24% of couples addressed to infertility program may be classified as Poor Ovarian Responder (POR).

Objective: To evaluate whether the repeated luteal phase stimulation (Second Step) permits a significantly higher number of oocytes retrieved in POR when compared to conventional follicular stimulation.

Interventions: The follicular phase stimulation is conduced according to a standardized Antagonist protocol or Short protocol (with GnRH agonist) using recombinant or urinary gonadotropins (starting dose 300 or 450 UI) or a long lasting recombinant gonadotropin (Corifollitropin alfa 150 mcg).

Two - six days after the first oocyte retrieval a second gonadotropin stimulation will be started with a GnRH antagonist protocol (the stimulation will be started with 250 UI of human menopausal gonadotropin (hMG) and a GnRH antagonist (GnRH-an) 0,25 mg\die will be administered when the leading follicle is ≥ 14 mm until hCG (human chorionic gonadotropin) criteria are met. When at least two follicles had reached 17-18 mm in diameter, ovulation will be triggered with a single subcutaneous bolus of urinary human chorionic gonadotropin (10.000 UI ) and oocyte retrieval will be performed after 35 hours.

Two or Three months after the second oocyte retrieval the Embryo transfer (ET) will be performed after endometrial preparation with Estradiol Valerate and intramuscular Progesterone.

Study Overview

Status

Unknown

Conditions

Intervention / Treatment

Detailed Description

Reduced ovarian reserve and the consequent poor ovarian response are very recurent in infertile patients, indeed a percentage of 10%-24% of couples addressed to infertility program may be classified as Poor Ovarian Responder (POR).

Poor ovarian response and reduced ovarian reserve can be caused by different factors such as advanced female age, smoking, autoimmune diseases, aneuploidies and genetic diseases or can be idiopathic.

An Eshre ( European Society of Human Reproduction and Embryology) consensus in 2011 established the "Bologna Criteria" that consented a standardize definition of poor ovarian response (POR).

According with the Bologna Criteria we can diagnose a Poor Ovarian Response or an expected Poor Ovarian Response when at least two of the following three features are present:

  • Advanced maternal age (≥40 years) or any other risk factor for POR;
  • A previous POR (≤3 oocytes with a conventional stimulation protocol);
  • An abnormal ovarian reserve test (i.e. AFC -Antral Follicular Count- 5-7 follicles or AMH ,0.5-1.1 ng/ml). The diagnosis and the prediction of poor ovarian response consent the selection of the best treatment with the aim of the retrieval of an high number of oocytes.

A lot of treatment have been proposed to optimize in vitro fertilization outcomes in POR (high dosage of Gonadotropins; short protocol, administration of androgens or Aromatase Inhibitors, administration of Growth Hormone and the repeated luteal phase stimulation).

The Luteal Phase Stimulation was initially proposed for fertility preservation procedures, but in last years is used in POR patients too. The recently diffused "wave theory" support this technique. According to the wave theory two or three cohorts of antral follicles are recruited during the follicular and luteal phase of each ovarian cycle and in one of this follicular wave will be selected the dominant follicle.

A trial performed in 2014 (Kuang et al, 2014) pubblished results of repeated luteal phase stimulation (Shanghai Protocol) showing that double ovarian stimulations in the same menstrual cycle provide more opportunities for retrieving oocytes in poor responders. More recently another trial (Ubaldi et al 2016) did not observe significant differences in term of number of oocytes retrieved and euploid blastocyst rate from follicular versus luteal phase stimulation.

Objective: To evaluate whether the repeated luteal phase stimulation (Second Step) permits a significantly higher number of oocytes retrieved in POR when compared to conventional follicular stimulation.

Interventions: The follicular phase stimulation is conduced according to a standardized Antagonist protocol or Short protocol (with GnRH agonist) using recombinant or urinary gonadotropins (starting dose 300 or 450 UI) or a long lasting recombinant gonadotropin (Corifollitropin alfa 150 mcg) from the second day of the menstrual cycle. When at least two follicles had reached 17-18 mm in diameter, ovulation will be triggered with a single subcutaneous bolus of urinary human chorionic gonadotropin (10.000 UI ) and oocyte retrieval will be performed after 35 hours.

Two - six days after the first oocyte retrieval a second gonadotropin stimulation will be started with a GnRH antagonist protocol (the stimulation will be started with 250 UI of human menopausal gonadotropin (hMG) and a GnRH antagonist (GnRH-an) 0,25 mg\die will be administered when the leading follicle is ≥ 14 mm until hCG criteria are met). When at least two follicles had reached 17-18 mm in diameter, ovulation will be triggered with a single subcutaneous bolus of urinary human chorionic gonadotropin (10.000 UI ) and oocyte retrieval will be performed after 35 hours.

Two or Three months after the second oocyte retrieval the Embryo transfer (ET) will be performed after endometrial preparation with Estradiol Valerate and intramuscular Progesterone.

Study Type

Observational

Enrollment (Anticipated)

50

Contacts and Locations

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

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

  • Child
  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Genders Eligible for Study

Female

Sampling Method

Non-Probability Sample

Study Population

Infertil Women classified as Poor Ovarian Responder according with Bologna Criteria (2011) for which an IVF is indicated and in which the number of oocyte retrieved with First oocyte retrieval ≤ 2

Description

Inclusion Criteria:

  • Antral Follicular Count ≤7 follicles
  • Number of oocyte retrieved with First oocyte retrieval ≤ 2

Exclusion Criteria:

  • Antral follicular Count < 7
  • Anti-Müllerian hormone (AMH) >1.1 ng \mL
  • Number of oocyte retrieved with First oocyte retrieval > 2
  • Absence of antral follicles after First oocyte 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
Intervention / Treatment
Follicular Phase
Procedure: Follicular Phase
The follicular phase stimulation is conduced according to a standardized Antagonist protocol or Short protocol (with GnRH agonist) using recombinant or urinary gonadotropins (starting dose 300 or 450 UI) or a long lasting recombinant gonadotropin (Corifollitropin alfa 150 mcg) from the second day of the menstrual cycle. When at least two follicles had reached 17-18 mm in diameter, ovulation will be triggered with a single subcutaneous bolus of urinary human chorionic gonadotropin (10.000 UI ) and oocyte retrieval will be performed after 35 hours.
Other Names:
  • First Step
Luteal Phase
Procedure: Luteal Phase
Two - six days after the first oocyte retrieval a second gonadotropin stimulation will be started with a GnRH antagonist protocol (the stimulation will be started with 250 UI of human menopausal gonadotropin (hMG) and a GnRH antagonist (GnRH-an) 0,25 mg\die will be administered when the leading follicle is ≥ 14 mm until hCG criteria are met). When at least two follicles had reached 17-18 mm in diameter, ovulation will be triggered with a single subcutaneous bolus of urinary human chorionic gonadotropin (10.000 UI ) and oocyte retrieval will be performed after 35 hours.
Other Names:
  • Second Step

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of oocyte Retrieved
Time Frame: 15 days after the Second oocyte retrieval
Number of oocyte Retrieved after the first oocyte retrieval vs Number of oocyte Retrieved after the second oocyte retrieval
15 days after the Second oocyte retrieval

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of Embryos Obtained
Time Frame: 15 days after the Second oocyte retrieval
Number of Embryos Obtained after the Follicular Phase Stimulation and intracytoplasmic sperm injection vs Number of Embryos obtained after Luteal Phase Stimulation and intracytoplasmic sperm injection
15 days after the Second oocyte retrieval

Collaborators and Investigators

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

Sponsor

Università degli Studi 'G. d'Annunzio' Chieti e Pescara

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 (Actual)

September 1, 2017

Primary Completion (Anticipated)

March 30, 2019

Study Completion (Anticipated)

September 1, 2019

Study Registration Dates

First Submitted

March 21, 2018

First Submitted That Met QC Criteria

March 21, 2018

First Posted (Actual)

March 29, 2018

Study Record Updates

Last Update Posted (Actual)

April 2, 2018

Last Update Submitted That Met QC Criteria

March 30, 2018

Last Verified

March 1, 2018

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • Second Step 1

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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