Baselines in Reproductive Disorders

Normal reproductive cycles in women require the integrated function of the hypothalamus,
pituitary and ovaries. The hypothalamic component of the reproductive system can be assessed
directly in lower animal species by measurement of gonadotropin releasing hormone (GnRH)
directly from pituitary portal blood and recording of multiunit activity from the median
eminence of the hypothalamus, providing direct information about the physiology of GnRH
secretion and the activity of the GnRH pulse generator. However, these techniques are not
feasible in the human. In addition, measurement of GnRH levels in peripheral blood does not
accurately reflect hypothalamic GnRH secretion. Thus, indirect methods must be used to gain
insight into hypothalamic function in the human.

In the human, pulsatile luteinizing hormone (LH) secretion has been used as a mirror of
hypothalamic GnRH secretion, citing comparative data from the rat, sheep, and non-human
primate which indicate that pulses of LH are directly linked to antecedent pulses of GnRH.
LH secretion thus provides an estimate of the underlying frequency of GnRH pulse generator
activity provided that the assay is sufficiently precise, with a low coefficient of
variation, and that blood sampling is frequent enough to accurately reflect the underlying
frequency of episodic GnRH pulsatility. The use of pulsatile secretion of the free alpha
subunit (FAS) of the gonadotropins has recently been proposed as an alternative and improved
marker of GnRH secretion in the human due to a half-life of 15 minutes versus 20 to 40
minutes for LH. Despite the dual control of FAS by GnRH and thyroid releasing hormone (TRH),
our studies have shown that the pulsatile component of FAS secretion is driven solely by
GnRH in euthyroid subjects. Such studies have indicated:

1. the nearly complete concordance of pulses of FAS with those of LH in normal women, and
in GnRH-deficient subjects undergoing GnRH replacement;

2. the absence of pulsatile secretion of FAS in GnRH-deficient subjects; and

3. the abolition of pulsatile FAS secretion in concert with that of LH following
administration of a GnRH antagonist in normal and postmenopausal women.

We have proposed that abnormalities in the pulsatile secretion of GnRH underlie many
reproductive abnormalities and that these may explain the clinical variability, which exists
even within a given diagnostic category. In this protocol, we have sought to define the
specific neuroendocrine profile in patients with amenorrhea or oligomenorrhea. In some
patients, the results of these studies can then correlated with clinical outcomes of
ovulation induction protocols and with genotype information. We have examined the spectrum
of abnormal patterns of LH (and by inference GnRH) secretion in women with secondary
hypogonadotropic hypogonadism. In 73 studies in 50 women, it has been determined that the
most common neurosecretory defect is low frequency/low amplitude followed by normal
frequency/normal amplitude, apulsatile, and low amplitude/normal frequency. Of patients
studied on several occasions, 75% demonstrated at least 2 different patterns of LH secretion
and 33% reverted at least once to a normal pattern of secretion. Study of the baseline
patterns of LH secretion in patients with acquired GnRH deficiency/acquired hypothalamic
hypogonadism (AHH) indicates that this group of patients has either an apulsatile pattern or
a pattern of low amplitude LH pulses in comparison with normal women in the early follicular
phase (matched for ovarian steroid levels). In these patients, the specific LH pattern does
not predict response to pulsatile GnRH used for ovulation induction. FAS is apulsatile in
the majority of patients with primary amenorrhea and absent LH pulses providing further
support for the hypothesis that the pulsatile component of FAS secretion is primarily driven
by GnRH in euthyroid patients despite the dual control of FAS by GnRH and TRH. As in men
with presumed GnRH deficiency, occasional patients with absent LH pulses will have FAS
pulses. These interesting patients are being further evaluated with respect to their pattern
of TSH secretion and the bioactivity of their LH.

Inclusion Criteria:

- Healthy women between the ages of 16-45 years

- Negative pregnancy test

- On no gonadal steroid preparations for at least 3 months, with the exception of the
idiopathic hypogonadotropic hypogonadism (IHH) group, they should be off gonadal
steroid for at least 4 weeks

The following test will be performed if they had not been done in the last 2 months

- Normal blood count

- Normal thyroid function test

Exclusion Criteria:

- Hemoglobin levels less than 11 gm/dL

- Positive pregnancy test

- Abnormal thyroid function

- Abnormal MRI (IHH)