Last updated on February 2018

Baselines in Reproductive Disorders


Brief description of study

The purpose of the study is to explore the way in which gonadotropins (pituitary hormones) are released into the body. The knowledge acquired in this study will be used for the diagnosis and treatment of reproductive endocrine disorders.

We seek to investigate the baseline characteristics of the GnRH-induced gonadotropin pulsations of patients with the following diagnoses:

  • Hypothalamic Amenorrhea (HA)
  • Idiopathic hypogonadotropic hypogonadism (IHH)
  • Polycystic ovarian disease (PCOD)
  • Acquired hypogonadotropic hypogonadism (AHH)
  • Premature Ovarian Failure (POF)

**WE ARE CURRENTLY RECRUITING ONLY SUBJECTS WITH A DIAGNOSIS OF IHH.**

This has been an extremely productive and pivotal protocol in the studies of female reproductive physiology and pathophysiology and continues to be critical for defining the neuroendocrine abnormalities in patients with reproductive disorders. In some cases, it is also helpful in the planning of subsequent therapy if so desired.

It is important to note that minors have been included in this protocol, as many patients are extremely anxious to know more about their neuroendocrine disorder. With minors who would like to know if their disorder is correctable, this protocol may be followed up with administration of pulsatile gonadotropin-releasing hormone (GnRH).

Detailed Study Description

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.

Clinical Study Identifier: NCT00456274

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Natalie Shaw, MD

Massachusetts General Hospital
Boston, MA United States
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