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Severe LH Suppressed Patients After Administration of a GnRH Antagonist (OPTOMALH)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01936077
Recruitment Status : Completed
First Posted : September 5, 2013
Last Update Posted : September 5, 2013
Maccabi Healthcare Services, Israel
Information provided by (Responsible Party):
shahar kol, Assuta Hospital Systems

Brief Summary:

The ideal stimulation protocol for ovarian stimulation is under constant debate, as we gain more pharmacological control over the patient hormonal milieu. Specifically, the debate focuses around the ideal LH levels. The concept of an "LH window" was suggested.

The need for a threshold level of LH is clearly demonstrated in hypogonado-tropic hypogonadism patients, but also in cycling patients receiving high doses of GnRH antagonist. The Ganirelix dose finding study demonstrated very low implantation rates in the high dose groups (1 mg, 2 mg).

The stimulation dynamics in these patients were remarkable for very low E2 and LH levels on the day of hCG. In fact, a functional state of hypogonadotropic hypogonadism is achieved, explaining the poor clinical results (1.5% implantation rate under 2 mg Ganirelix). The same protocol was repeated with added Luveris resulting in excellent pregnancy rates.

The recommended daily dose of GnRH antagonist is 0.25 mg which on the average provides a protection from premature LH surge, with moderate suppression of LH. Therefore, most patients do not need supplemented LH after the antagonist is initiated.

However, there is a subgroup of patients who hyper-respond to the antagonist (in 0.25 mg dose) with a sharp decrease in LH. This explains contradictory findings in the available studies. The basic assumption in the background of this proposal is that there is a wide range of pituitary responses to GnRH antagonist. Obeying a bell-shape curve, most women have an average response, however, some hypo-respond might ovulate prematurely, and others hyper-respond. In the latter cases, pituitary response will behave as if exposed to a higher dose.

How to identify an exposure to a presumed higher dose?

Below is a figure from the original paper. A close look indicates that the immediate response to all Ganirelix doses are similar in terms of LH drop, however, the big difference lies in the pituitary recovery 24 hours post Ganirelix dose.

While small doses allow for a quick recovery to almost pre-treatment LH levels, high doses result in incomplete recovery. Hence, it is reasonable to speculate that the high response to 0.25 mg dose will lead to slow or incomplete recovery of LH levels 24 hours post the initial dose.

It is estimated that about 15% of patients are antagonist hyper-responders. Efforts to individualize patient protocol must target this group as candidates for supplemented LH. This estimate is similar to study findings: Huirne et al Human Reproduction 2005, 20: 359.

Condition or disease Intervention/treatment Phase
Infertility, Female Infertility, Male Infertility Drug: Recombinant LH (Luveris) Phase 4

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 50 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: To Define the Individual Need of Exogenous LH During Ovarian Stimulation for Severe LH Suppressed Patients After Administration of a GnRH Antagonist
Study Start Date : June 2010
Actual Primary Completion Date : May 2013
Actual Study Completion Date : August 2013

Arm Intervention/treatment
Experimental: GnRH antagomnist hyper-responders
Those defined as hyper-responders will be given recombinant LH.
Drug: Recombinant LH (Luveris)
150 IU recombinant LH daily.
Other Name: Luveris

Primary Outcome Measures :
  1. The primary endpoint will be the proportion of patients who, after receiving Cetrotide after 4 or 5 days of Gonal -F stimulation, are severely down-regulated. [ Time Frame: 24 hours after first administration of Cetrotide. ]
    If LH drops more than 50% from its baseline (as measured before Cetrotide) the patient is defined as "Cetrotide hyper-responder"

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Ages Eligible for Study:   18 Years to 39 Years   (Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • 1. The patient is eligible for IVF and will be treated according to the Summary of Product Characteristics (SmPC) and routine practice in participating centres.

    2. The patient must be willing and able to comply with the protocol for the duration of the study.

    3. The patient has given written informed consent with the understanding that the consent may be withdrawn by her at any time without prejudice for her future medical care.

    4. Must be hyper-responder to antagonist according definition

Exclusion Criteria:

  1. Ovarian, uterine or mammary cancer.
  2. Tumours of the hypothalamus and pituitary gland.
  3. Uterine myoma requiring treatment.
  4. Ovarian enlargement or cyst of unknown aetiology.
  5. A clinically significant systemic disease.
  6. Abnormal gynaecological bleeding of undetermined origin.
  7. Known allergy or hypersensitivity to human gonadotrophin preparations.
  8. Entered previously into this study or simultaneous participation in another clinical study.
  9. Age > 39 yrs,
  10. BMI > 32 kg/m2,
  11. Patient with no cycles: PCOS or an anovulatory patient. -

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01936077

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Women Health Center, Maccabi Health Services
Haifa, Israel
Sponsors and Collaborators
Assuta Hospital Systems
Maccabi Healthcare Services, Israel

Publications automatically indexed to this study by Identifier (NCT Number):
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Responsible Party: shahar kol, Director, fertility clinic, Women Health Center, Haifa, Israel, Assuta Hospital Systems Identifier: NCT01936077     History of Changes
Other Study ID Numbers: 2010036
First Posted: September 5, 2013    Key Record Dates
Last Update Posted: September 5, 2013
Last Verified: September 2013
Keywords provided by shahar kol, Assuta Hospital Systems:
Infertility, IVF, ovarian stimulation, rec LH, GnRH antagonist
Additional relevant MeSH terms:
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Infertility, Male
Infertility, Female
Genital Diseases, Male
Genital Diseases, Female