HealthyPhase 2/3NCT00386022
The Effects of Aging and Estrogen on the Pituitary
A Phase 2/3 study testing GnRH, NAL-GLU GnRH antagonist and Estrogen patch in people with Healthy, run by Massachusetts General Hospital at 1 site in United States.
Trial summary
The purpose of this study is to study the effects of aging and estrogen on the brain. Specifically, this study will examine how the hypothalamus signals the pituitary gland to secrete reproductive hormones and how that changes with aging. Read more about this study
- Who is it for?
- Ages 45 to 80 years, women onlyHealthy volunteers can take part
- Conditions the study is for
- Healthy
- What is being tested?
- GnRH, NAL-GLU GnRH antagonist and Estrogen patch
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 19 participants
- Where
- 1 siteUnited States
- Study dates
- Jan 2002to Jan 2018
- Phase
- Phase 2/3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 45 to 80 years
- Women only
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- 45-55 or 70-80 years old
- History of natural menopause defined by the absence of menses for at least 12 months (or history of surgical menopause defined as bilateral oophorectomy) and a FSH level >26 IU/L
- On no hormonal medication or herbal supplements and/or over the counter menopause therapy for a minimum of 2 months prior to study
- Normal thyroid stimulating hormone, prolactin, factor V Leiden, and complete blood count - Normal blood urea nitrogen and creatinine (< 2 times the upper limit of normal)
- basal metabolic index ≤ 30
- Non-smokers or smoke less than 10 cigarettes/day
Who cannot join
- Absolute contraindications to the use of physiologic replacement doses of estrogen, including a negative screening mammogram within the past 24 months
- History of coronary artery disease
- On medications thought to act centrally on the GnRH pulse generator
- Past history of hypersensitivity or allergy to narcotics, vancomycin, muscle relaxants, aspirin, and/or anaphylactic reaction(s) to other drugs
- Prior history of breast cancer and/or blood clots
Trial locations and contacts
1 site in 1 country.
United States1 site
Massachusetts General Hospital
Boston, Massachusetts, 02114
About this study
Official title: The Effect of Aging on the Isolated Pituitary Response to Gonadotropin Releasing Hormone at Baseline and With Low Dose Estrogen Administration
The purpose of this study is to study the effects of aging and estrogen on the brain. Specifically, this study will examine how the hypothalamus signals the pituitary gland to secrete reproductive hormones and how that changes with aging.
Read the detailed description
Although it is clear that loss of ovarian function plays a major role in the menopause in women, there is evidence from animal studies that primary age-related hypothalamic and pituitary changes may also contribute to reproductive aging. Complete cessation of ovarian function results in the loss of negative feedback of ovarian steroids and inhibin on the hypothalamic and pituitary components of the reproductive axis. An increase in serum levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) occurs in postmenopausal women with removal of negative ovarian feedback. However, levels of LH and FSH after menopause decline steadily as a function of age in most though not all studies.
The current study is designed to determine: 1) whether negative feedback on LH and FSH occurs at the pituitary; and 2) whether there is an effect of aging on estrogen negative feedback at the pituitary. Younger and older postmenopausal women underwent a baseline study and a second identical study after a month of low dose estrogen replacement. The study protocol consisted of the following: 1) administration of a GnRH antagonist (Nal-Glu at 150 mg/kg that blocks endogenous GnRH so that the dose and interval of pituitary exposure to GnRH are precisely controlled; 2) beginning 8 hours following GnRH antagonist administration (at a time when LH had reached its nadir following GnRH receptor blockade), administration of 4 graded doses of GnRH (25, 75, 250 and 750 ng/kg every 2 hours with 2 hours of blood draws following each dose). Blood was sampled every 30 min for 4 hours before antagonist administration, every 30 min for the following 7 hours and then every 10 min until the completion of the study.
- Conditions
- Healthy
- Being tested
- GnRH, NAL-GLU GnRH antagonist, Estrogen patch
- Keywords
- Gonadotropin-releasing hormone, Estrogens, postmenopausal women, Pituitary hormones
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
GnRHDrug
Also called gonadotropin-releasing hormone, Factryl
GnRH doses of 25, 75, 250 and 750 ng/kg will be given IV every 4 hr at baseline and after transdermal estradiol
NAL-GLU GnRH antagonistDrug
Also called GnRH antagonist
A single subcutaneous injection of the NAL-GLU GnRH antagonist at a dose of 150 mcg/kg before and after transdermal estradiol
Estrogen patchDrug
Also called Climara, Estraderm
transdermal estrogen patches 0.05mg/day, changing the patch every 86 hr in second part of sequential study
| Study group | Role | What they receive |
|---|---|---|
| Young postmenopausal women | Experimental | intervention: graded doses of GnRH following NAL-GLU GnRH antagonist administration with or without transdermal estrogen patch Receives: Drug: GnRH; Drug: NAL-GLU GnRH antagonist; Drug: Estrogen patch |
| Older postmenopausal women | Experimental | intervention: graded doses of GnRH following NAL-GLU GnRH antagonist administration with or without transdermal estrogen patch Receives: Drug: GnRH; Drug: NAL-GLU GnRH antagonist; Drug: Estrogen patch |
What is being measured
The primary outcome is the main question the study is designed to answer.
Pituitary Response to GnRH
Baseline LH and FSH responses to each of 4 GnRH doses - peak to nadir amplitude expressed as percent (%) change from nadir
Measured: Peak hormone level within 2 hours post GnRH doses
Effect of Estrogen on Pituitary Response to GnRH
LH and FSH responses to each of 4 GnRH doses, expressed as change in amplitude [amp] from peak to nadir between plus estrogen and baseline conditions
Measured: Peak hormone level within 2 hours post GnRH doses
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted11 Oct 2006 (estimated)
- Study startJan 2002
- Primary completionJan 2012
- Study completionJan 2018 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for HealthyStudies of the same condition, open and under way.
- More trials run by Massachusetts General HospitalThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2/3
- Primary purpose
- Other
- Allocation
- Randomised
- Intervention model
- Sequential
- Model description
- The study will is considered sequential as participants were studied at baseline and after one month of low-dose estrogen. Randomization refers to randomization of the order of doses of GnRH between participants.
- Masking
- None (open label)
- Enrolment
- 19 participants (actual)
Sponsor and investigators
- Lead sponsor
- Massachusetts General Hospital
- Sponsor type
- University, hospital or other
- Collaborators
- National Institute on Aging (NIA)
- Responsible party
- Principal investigator, Janet E. Hall, MD, Massachusetts General Hospital
- Investigators
- Janet E Hall, M.D., Principal investigator, Massachusetts General Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00386022
- Sponsor's protocol ID
- 2000-P-002498
- Other IDs
- R01AG013241
- Status last verified
- Apr 2017
- First submitted
- 6 Oct 2006
- Last updated
- 13 Apr 2017
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- Individual data sharing
- Yes: Coded data with identifying information can be requested by contacting the PI.
Publications
Shaw ND, Histed SN, Srouji SS, Yang J, Lee H, Hall JE. Estrogen negative feedback on gonadotropin secretion: evidence for a direct pituitary effect in women. J Clin Endocrinol Metab. 2010 Apr;95(4):1955-61. doi: 10.1210/jc.2009-2108. Epub 2010 Feb 4.
PubMed 20133465Shaw ND, Srouji SS, Histed SN, McCurnin KE, Hall JE. Aging attenuates the pituitary response to gonadotropin-releasing hormone. J Clin Endocrinol Metab. 2009 Sep;94(9):3259-64. doi: 10.1210/jc.2009-0526. Epub 2009 Jun 23.
PubMed 19549740
Study at a glance
From the registry record, last updated by the sponsor on 13 Apr 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- The Effect of Aging on the Isolated Pituitary Response to Gonadotropin Releasing Hormone at Baseline and With Low Dose Estrogen Administration
- ClinicalTrials.gov ID
- NCT00386022
- Acronym / sponsor ID
- 2000-P-002498
- Conditions
- Healthy
- Keywords
- Gonadotropin-releasing hormone, Estrogens, postmenopausal women, Pituitary hormones
- Phase
- Phase 2/3
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 19 participants (actual)
- Lead sponsor
- Massachusetts General HospitalUniversity, hospital or other
- Collaborators
- National Institute on Aging (NIA)
- Study start
- Jan 2002
- Primary completion
- Jan 2012 (actual)
- Study completion
- Jan 2018 (estimated)
- First posted
- 11 Oct 2006 (estimated)
- Results
- Posted 13 Apr 2017
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The purpose of this study is to study the effects of aging and estrogen on the brain. Specifically, this study will examine how the hypothalamus signals the pituitary gland to secrete reproductive hormones and how that changes with aging.
Detailed description
Although it is clear that loss of ovarian function plays a major role in the menopause in women, there is evidence from animal studies that primary age-related hypothalamic and pituitary changes may also contribute to reproductive aging. Complete cessation of ovarian function results in the loss of negative feedback of ovarian steroids and inhibin on the hypothalamic and pituitary components of the reproductive axis. An increase in serum levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) occurs in postmenopausal women with removal of negative ovarian feedback. However, levels of LH and FSH after menopause decline steadily as a function of age in most though not all studies.
The current study is designed to determine: 1) whether negative feedback on LH and FSH occurs at the pituitary; and 2) whether there is an effect of aging on estrogen negative feedback at the pituitary. Younger and older postmenopausal women underwent a baseline study and a second identical study after a month of low dose estrogen replacement. The study protocol consisted of the following: 1) administration of a GnRH antagonist (Nal-Glu at 150 mg/kg that blocks endogenous GnRH so that the dose and interval of pituitary exposure to GnRH are precisely controlled; 2) beginning 8 hours following GnRH antagonist administration (at a time when LH had reached its nadir following GnRH receptor blockade), administration of 4 graded doses of GnRH (25, 75, 250 and 750 ng/kg every 2 hours with 2 hours of blood draws following each dose). Blood was sampled every 30 min for 4 hours before antagonist administration, every 30 min for the following 7 hours and then every 10 min until the completion of the study.
Study design
- Primary purpose
- Other
- Allocation
- Randomised
- Intervention model
- Sequential
- Masking
- None (open label)
- Number of arms
- 2
- Model description
- The study will is considered sequential as participants were studied at baseline and after one month of low-dose estrogen. Randomization refers to randomization of the order of doses of GnRH between participants.
| Arm | Type | Receives |
|---|---|---|
| Young postmenopausal women | Experimental | Drug: GnRH, Drug: NAL-GLU GnRH antagonist, Drug: Estrogen patchintervention: graded doses of GnRH following NAL-GLU GnRH antagonist administration with or without transdermal estrogen patch |
| Older postmenopausal women | Experimental | Drug: GnRH, Drug: NAL-GLU GnRH antagonist, Drug: Estrogen patchintervention: graded doses of GnRH following NAL-GLU GnRH antagonist administration with or without transdermal estrogen patch |
Who may qualify
- Ages
- 45 to 80 years
- Sex
- Female only
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (6 listed)
- 45-55 or 70-80 years old
- History of natural menopause defined by the absence of menses for at least 12 months (or history of surgical menopause defined as bilateral oophorectomy) and a FSH level >26 IU/L
- On no hormonal medication or herbal supplements and/or over the counter menopause therapy for a minimum of 2 months prior to study
- Normal thyroid stimulating hormone, prolactin, factor V Leiden, and complete blood count - Normal blood urea nitrogen and creatinine (< 2 times the upper limit of normal)
- basal metabolic index ≤ 30
Key exclusion criteria (5 listed)
- Absolute contraindications to the use of physiologic replacement doses of estrogen, including a negative screening mammogram within the past 24 months
- History of coronary artery disease
- On medications thought to act centrally on the GnRH pulse generator
- Past history of hypersensitivity or allergy to narcotics, vancomycin, muscle relaxants, aspirin, and/or anaphylactic reaction(s) to other drugs
- Prior history of breast cancer and/or blood clots
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| GnRHAlso: gonadotropin-releasing hormone, FactrylGnRH doses of 25, 75, 250 and 750 ng/kg will be given IV every 4 hr at baseline and after transdermal estradiol | Drug | Older postmenopausal women, Young postmenopausal women |
| NAL-GLU GnRH antagonistAlso: GnRH antagonistA single subcutaneous injection of the NAL-GLU GnRH antagonist at a dose of 150 mcg/kg before and after transdermal estradiol | Drug | Older postmenopausal women, Young postmenopausal women |
| Estrogen patchAlso: Climara, Estradermtransdermal estrogen patches 0.05mg/day, changing the patch every 86 hr in second part of sequential study | Drug | Older postmenopausal women, Young postmenopausal women |
Primary outcome
Pituitary Response to GnRH
Time frame: Peak hormone level within 2 hours post GnRH doses
Baseline LH and FSH responses to each of 4 GnRH doses - peak to nadir amplitude expressed as percent (%) change from nadir
Effect of Estrogen on Pituitary Response to GnRH
Time frame: Peak hormone level within 2 hours post GnRH doses
LH and FSH responses to each of 4 GnRH doses, expressed as change in amplitude [amp] from peak to nadir between plus estrogen and baseline conditions
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 13 Apr 2017.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Results publication: PubMed 20133465Shaw ND, Histed SN, Srouji SS, Yang J, Lee H, Hall JE. Estrogen negative feedback on gonadotropin secretion: evidence for a direct pituitary effect in women. J Clin Endocrinol Metab. 2010 Apr;95(4):1955-61. doi: 10.1210/jc.2009-2108. Epub 2010 Feb 4.
- Results publication: PubMed 19549740Shaw ND, Srouji SS, Histed SN, McCurnin KE, Hall JE. Aging attenuates the pituitary response to gonadotropin-releasing hormone. J Clin Endocrinol Metab. 2009 Sep;94(9):3259-64. doi: 10.1210/jc.2009-0526. Epub 2009 Jun 23.
- Individual participant dataSharing planned: Yes. Coded data with identifying information can be requested by contacting the PI.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Janet E Hall, M.D. principal investigator
Massachusetts General Hospital
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2/3 study testing GnRH, NAL-GLU GnRH antagonist and Estrogen patch in people with Healthy, run by Massachusetts General Hospital at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 5 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 13 Apr 2017. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 13 Apr 2017). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Pituitary Response to GnRH (time frame: Peak hormone level within 2 hours post GnRH doses). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00386022, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 13 Apr 2017.