Severe LH Suppressed Patients After Administration of a GnRH Antagonist
Status:
Completed
Trial end date:
2013-08-01
Target enrollment:
Participant gender:
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.