Pulsatile GnRH in Anovulatory Infertility
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| ClinicalTrials.gov Identifier: NCT00383656 |
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Recruitment Status :
Recruiting
First Posted : October 3, 2006
Last Update Posted : July 12, 2017
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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.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Hypogonadotropic Hypogonadism Amenorrhea Kallmann's Syndrome | Drug: GnRH Device: Pump | Phase 2 |
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 (Clinical Trial) |
| Estimated Enrollment : | 270 participants |
| Intervention Model: | Single Group Assignment |
| Masking: | None (Open Label) |
| Primary Purpose: | Treatment |
| Official Title: | Pulsatile GnRH in Anovulatory Infertility |
| Study Start Date : | January 1989 |
| Estimated Primary Completion Date : | September 2020 |
| Estimated Study Completion Date : | September 2020 |
| Arm | Intervention/treatment |
|---|---|
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Experimental: Pulsatile GnRH
All participants will be administered GnRH intravenously by means of a portable infusion pump that delivers boluses at specific intervals.
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Drug: GnRH
75 ng/kg GnRH IV
Other Names:
Device: Pump portable, infusion pump for GnRH
Other Name: mini-infusion pump |
- ovulation [ Time Frame: 1 pulsatile GnRH cycle ]LH surge or luteal phase progesterone > 5 ng/dL
- pregnancy [ Time Frame: 6 weeks ]serum HCG indicative of pregnancy
- LH [ Time Frame: 1st 7 days of treatment ]LH levels from days 1-7of treatment of treatment
- FSH [ Time Frame: 1st 7 days of treatment ]FSH levels from days 1-7 of treatment
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| Ages Eligible for Study: | 16 Years to 45 Years (Child, Adult) |
| Sexes Eligible for Study: | Female |
| Accepts Healthy Volunteers: | No |
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.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00383656
| Contact: Janet E Hall, M.D. | 617-726-1117 | jehall@mgh.harvard.edu |
| United States, Massachusetts | |
| Massachusetts General Hospital | Recruiting |
| Boston, Massachusetts, United States, 02114 | |
| Principal Investigator: | Janet E Hall, M.D. | Massachusetts General Hospital |
Additional Information:
Publications:
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 ( U.S. NIH Grant/Contract ) |
| First Posted: | October 3, 2006 Key Record Dates |
| Last Update Posted: | July 12, 2017 |
| Last Verified: | July 2017 |
| Individual Participant Data (IPD) Sharing Statement: | |
| Plan to Share IPD: | Yes |
| Plan Description: | Individual patient data will be shared across MGH and NIH protocols to which the participant consents. |
| Supporting Materials: |
Study Protocol Informed Consent Form (ICF) Clinical Study Report (CSR) |
| Time Frame: | For the duration of the study. |
| Access Criteria: | must be approved by the study PI |
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gonadotropin releasing hormone GnRH deficiency hypothalamic amenorrhea |
hypogonadotropic hypogonadism Kallman's syndrome infertility |
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Infertility Kallmann Syndrome Hypogonadism Amenorrhea Pathologic Processes Genital Diseases, Male Genital Diseases, Female Gonadal Disorders Endocrine System Diseases Menstruation Disturbances |
Disorder of Sex Development, 46,XY Disorders of Sex Development Urogenital Abnormalities Congenital Abnormalities Genetic Diseases, Inborn Hormones Prolactin Release-Inhibiting Factors Hormones, Hormone Substitutes, and Hormone Antagonists Physiological Effects of Drugs |