Pulsatile GnRH in Anovulatory Infertility

This study is currently recruiting participants. (see Contacts and Locations)
Verified July 2014 by Massachusetts General Hospital
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Janet E. Hall, MD, Massachusetts General Hospital
ClinicalTrials.gov Identifier:
NCT00383656
First received: September 29, 2006
Last updated: July 31, 2014
Last verified: July 2014
  Purpose

The purpose of this study is to explore the effects of synthetic gonadotropin-releasing hormone (GnRH) upon the pituitary and ovaries of women with infertility. Women diagnosed with GnRH deficiency, hypothalamic amenorrhea, acquired hypogonadic hypogonadism, or polycystic ovarian syndrome (PCOS) will participate in this study. It is hoped that administration of GnRH will lead to proper stimulation of the pituitary gland and to normal ovulation and menstruation.

**WE ARE CURRENTLY RECRUITING ONLY WOMEN WITH A DIAGNOSIS OF IDIOPATHIC HYPOGONADIC HYPOGONADISM (IHH)**

Pulsatile GnRH has been approved by the FDA for use in women with primary amenorrhea due to complete GnRH deficiency. The overall goals of this protocol are to continue to use pulsatile GnRH in GnRH-deficient women for ovulation induction and to examine specific physiologic hypotheses, which can only be addressed in this patient population, and to examine the efficacy of pulsatile GnRH for ovulation induction in other subsets of anovulatory patients.


Condition Intervention Phase
Hypogonadotropic Hypogonadism
Amenorrhea
Kallmann's Syndrome
Drug: synthetic gonadotropin releasing hormone (GnRH)
Device: Mini-infusion pump
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Pulsatile GnRH in Anovulatory Infertility

Resource links provided by NLM:


Further study details as provided by Massachusetts General Hospital:

Primary Outcome Measures:
  • presence of ovulation and/or pregnancy [ Time Frame: 1 pulsatile GnRH cycle ] [ Designated as safety issue: No ]

Estimated Enrollment: 270
Study Start Date: January 1989
Estimated Study Completion Date: September 2020
Estimated Primary Completion Date: September 2020 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
1 Drug: synthetic gonadotropin releasing hormone (GnRH)
75 ng/kg GnRH IV
Device: Mini-infusion pump
portable, infusion pump for GnRH

Detailed Description:

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.

  Eligibility

Ages Eligible for Study:   16 Years to 45 Years
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

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.

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00383656

Contacts
Contact: Natalie Shaw, MD 617-726-1895 nshaw@partners.org

Locations
United States, Massachusetts
Massachusetts General Hospital Recruiting
Boston, Massachusetts, United States, 02114
Sponsors and Collaborators
Massachusetts General Hospital
Investigators
Principal Investigator: Janet Hall, M.D. Massachusetts General Hospital
  More Information

Additional Information:
Publications:

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Janet E. Hall, MD, MD, Massachusetts General Hospital
ClinicalTrials.gov Identifier: NCT00383656     History of Changes
Other Study ID Numbers: 1999-P-004396, 5U54HD028138
Study First Received: September 29, 2006
Last Updated: July 31, 2014
Health Authority: United States: Food and Drug Administration
United States: Institutional Review Board

Keywords provided by Massachusetts General Hospital:
gonadotropin releasing hormone
GnRH deficiency
hypothalamic amenorrhea
hypogonadotropic hypogonadism
Kallman's syndrome
infertility

Additional relevant MeSH terms:
Amenorrhea
Hypogonadism
Infertility
Kallmann Syndrome
Syndrome
46, XY Disorders of Sex Development
Congenital Abnormalities
Disease
Disorders of Sex Development
Endocrine System Diseases
Genetic Diseases, Inborn
Genital Diseases, Female
Genital Diseases, Male
Gonadal Disorders
Menstruation Disturbances
Pathologic Processes
Urogenital Abnormalities
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Pharmacologic Actions
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on October 21, 2014