Pulsatile GnRH in Anovulatory Infertility

July 9, 2017 updated by: Janet E. Hall, MD, Massachusetts General Hospital

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 or acquired hypogonadic hypogonadism, 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 and other anovulatory women for ovulation induction and to examine specific physiologic hypotheses, which can only be addressed in this patient population.

Study Overview

Status

Unknown

Conditions

Intervention / Treatment

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.

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.

Study Type

Interventional

Enrollment (Anticipated)

270

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • United States
    • Massachusetts
      • Boston, Massachusetts, United States, 02114
        • Recruiting
        • Massachusetts General Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

14 years to 43 years (Child, Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

Female

Description

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, a deficient 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, BMI > 18 kg/m2 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:

Mitral valve prolapse with ballooning of the mitral valve will be cause for exclusion of the patient from intravenous GnRH treatment.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Pulsatile GnRH
All participants will be administered GnRH intravenously by means of a portable infusion pump that delivers boluses at specific intervals.
Drug: GnRH
75 ng/kg GnRH IV
Other Names:
  • gonaodtropin releasing hormone
  • GnRH pump
Device: Pump
portable, infusion pump for GnRH
Other Names:
  • mini-infusion pump

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
ovulation
Time Frame: 1 pulsatile GnRH cycle
LH surge or luteal phase progesterone > 5 ng/dL
1 pulsatile GnRH cycle

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
pregnancy
Time Frame: 6 weeks
serum HCG indicative of pregnancy
6 weeks

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
LH
Time Frame: 1st 7 days of treatment
LH levels from days 1-7of treatment of treatment
1st 7 days of treatment
FSH
Time Frame: 1st 7 days of treatment
FSH levels from days 1-7 of treatment
1st 7 days of treatment

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Massachusetts General Hospital

Collaborators

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

January 1, 1989

Primary Completion (Anticipated)

September 1, 2020

Study Completion (Anticipated)

September 1, 2020

Study Registration Dates

First Submitted

September 29, 2006

First Submitted That Met QC Criteria

September 29, 2006

First Posted (Estimate)

October 3, 2006

Study Record Updates

Last Update Posted (Actual)

July 12, 2017

Last Update Submitted That Met QC Criteria

July 9, 2017

Last Verified

July 1, 2017

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 1999-P-004396
  • 5U54HD028138 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

Yes

IPD Plan Description

Individual patient data will be shared across MGH and NIH protocols to which the participant consents.

IPD Sharing Time Frame

For the duration of the study.

IPD Sharing Access Criteria

must be approved by the study PI

IPD Sharing Supporting Information Type

  • Study Protocol
  • Informed Consent Form (ICF)
  • Clinical Study Report (CSR)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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