Pulsatile GnRH in Anovulatory Infertility

In comparison to the use of exogenous gonadotropins, pulsatile administration of GnRH has
many theoretical advantages for ovulation induction, including; 1) the ability to use the
patients' own gonadotropins for ovarian stimulation; 2) the ability to treat anovulatory
defects at their appropriate level, which most commonly is hypothalamic; 3) the ability to
maintain normal ovarian-pituitary feedback mechanisms to restrain endogenous FSH secretion,
as occurs normally in species that ovulate a single egg per cycle; 4) a resultant decrease
in the risks of multiple gestations and hyperstimulation; and 5) a decreased need for
intensive monitoring of ovarian function with an attendant decrease in costs.

When synthetic GnRH first became available for clinical study, there was not yet an adequate
understanding of the physiology of GnRH secretion in the human to support its potential
therapeutic application. As a result, early attempts at ovulation induction were
unsuccessful. It was soon appreciated that an episodic mode of delivery was essential for
normal pituitary stimulation by GnRH. Studies by our group and others which defined the
frequency of pulsatile GnRH secretion in normal women at different stages of the menstrual
were then key to designing a physiologic program of pulsatile GnRH administration that
resulted in successful ovulation induction in patients with GnRH deficiency. Additional
studies demonstrated that which replacement of GnRH using the subcutaneous route was
adequate to reproduce normal physiology in GnRH-deficient men, the intravenous route was
superior in women. We have now determined the dose of GnRH which is appropriate for the
majority of women as 75 ng/kg, a dose which induces ovulation of a single dominant follicle,
followed by normal luteal phase dynamics.

A number of investigators including us have sought to define the specific subgroups likely
to achieve the greatest benefit from this form of therapy. However, there are many questions
which remain unanswered and that we are currently addressing. We are specifically interested
in understanding why there is variability in the dose of GnRH required by apparently
GnRH-deficient women and have recently determined that one of our patients who required a
significantly higher dose of GnRH to reproduce normal cycle dynamics, had a mutation of the
GnRH receptor rather than a deficiency of GnRH itself. We have recently determined that the
response of gonadotropin free a-subunit may help to refine the phenotype in patients with
idiopathic hypogonadotropic hypogonadism.

In addition, we are actively recruiting patients with polycystic ovarian syndrome (PCOS).
Patients with PCOS have a more variable response to pulsatile GnRH than do other subsets of
anovulatory patients and we are seeking to determine the specific patient characteristics,
which predict success. This is important as this group of patients are particularly
challenging in terms of ovulation induction with gonadotropins, being susceptible to ovarian
hyperstimulation, cycle cancellation and/or multiple gestation. One of the major factors
associated with anovulation is insulin resistance with compensatory hyperinsulinemia.
Improving insulin resistance, using an insulin-sensitizing agent as metformin, has been
shown to improve ovulatory function in patients with PCOS undergoing ovulation induction
with clomiphene or exogenous gonadotropins. The combination of metformin with pulsatile GnRH
will be addressed in this population.

It is important to note that minors have been included in this protocol, as many patients
are extremely anxious to know whether they respond normally to pulsatile GnRH even though
they may not be interested in conceiving at the time. This is particularly true of patients
who have survived childhood cancers and associated surgery and/or radiation in whom a normal
response to pulsatile GnRH can be a very positive experience. Minors with PCOS will not be
administered Metformin as part of this protocol.

Inclusion Criteria:

- Women and minors with GnRH deficiency or idiopathic hypogonadotropic hypogonadism
(IHH) will have a history of primary amenorrhea, no evidence of abnormalities in
other hormonal axes, an apulsatile pattern of luteinizing hormone (LH) and/or free
alpha subunit (FAS) secretion on baseline sampling and a normal cranial CT or MRI.

- Women and minors with hypothalamic amenorrhea will have a history of secondary
amenorrhea of at least six months duration with low or normal gonadotropins or a
history of primary amenorrhea in the presence of pulsatile patterns of LH or FAS on
baseline frequent sampling studies, weight between the 10th and 90th percentile for
height according to the Sargent scale and normal testosterone and prolactin levels.

- Women and minors with acquired hypogonadotropic hypogonadism will have a history of
hypothalamic or pituitary tumor treated with surgery alone or in combination with
radiotherapy or a history of hypothalamic irradiation as adjunctive therapy for
leukemia or craniofacial neoplasms. There must be a minimum of 2 years since
irradiation and no gonadal radiation. For the previous two months, patients will be
euthyroid on thyroid replacement if needed, normoprolactinemic on dopamine agonists
if needed, and receiving physiologic glucocorticoid replacement if needed.

Subjects will be otherwise healthy women and female minors between the ages of 16 and 45
years who have not been on gonadal steroid preparations for at least 1 month. Subjects
will have normal complete blood count (hemoglobin greater than or equal to 11.5gm/dl) and
thyroid function tests and a negative pregnancy test.

Exclusion Criteria:

Patients will be screened for clinical evidence of mitral valve prolapse and those in whom
it is suspected will undergo a cardiac ultrasound evaluation. The presence of ballooning
of the mitral valve will be cause for exclusion of the patient from intravenous GnRH
treatment.