Severe LH Suppressed Patients After Administration of a GnRH Antagonist (OPTOMALH)
|ClinicalTrials.gov Identifier: NCT01936077|
Recruitment Status : Completed
First Posted : September 5, 2013
Last Update Posted : September 5, 2013
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|
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||50 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|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|
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
- 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"
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01936077
|Women Health Center, Maccabi Health Services|