Severe LH Suppressed Patients After Administration of a GnRH Antagonist

NCT ID: NCT01936077

Last Updated: 2013-09-05

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 50 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2010-06-30
• Study Completion Date: 2013-08-31

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.

Conditions

Infertility, Female Infertility, Male Infertility

Keywords

Infertility, IVF, ovarian stimulation, rec LH, GnRH antagonist

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

GnRH antagomnist hyper-responders

Those defined as hyper-responders will be given recombinant LH.

Group Type: EXPERIMENTAL

Recombinant LH (Luveris)

Intervention Type: DRUG

150 IU recombinant LH daily.

Interventions

Recombinant LH (Luveris)

150 IU recombinant LH daily.

Intervention Type: DRUG

Other Intervention Names

Luveris

Eligibility Criteria

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. -

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 39 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

Maccabi Healthcare Services, Israel

OTHER

Sponsor Role: collaborator

Assuta Hospital Systems

OTHER

Sponsor Role: lead

Responsible Party

shahar kol

Director, fertility clinic, Women Health Center, Haifa, Israel

Responsibility Role: PRINCIPAL_INVESTIGATOR

Locations

Women Health Center, Maccabi Health Services

Haifa, , Israel

Countries

Israel

References

Kol S. Individualized Treatment from Theory to Practice: The Private Case of Adding LH during GnRH Antagonist-based Stimulation Protocol. Clin Med Insights Reprod Health. 2014 Oct 14;8:59-64. doi: 10.4137/CMRH.S17788. eCollection 2014.

Reference Type: DERIVED

PMID: 25452708 (View on PubMed)

Other Identifiers

2010036

Identifier Type: -

Identifier Source: org_study_id