Healthy
Conditions
Keywords
Gonadotropin-releasing hormone, Estrogens, postmenopausal women, Pituitary hormones
Brief 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.
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.
Interventions
DRUGGnRH
GnRH doses of 25, 75, 250 and 750 ng/kg will be given IV every 4 hr at baseline and after transdermal estradiol
A single subcutaneous injection of the NAL-GLU GnRH antagonist at a dose of 150 mcg/kg before and after transdermal estradiol
DRUGEstrogen patch
transdermal estrogen patches 0.05mg/day, changing the patch every 86 hr in second part of sequential study
Sponsors
National Institute on Aging (NIA)
Massachusetts General Hospital
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
OTHER
Masking
NONE
Intervention 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.
Eligibility
Sex/Gender
FEMALE
Age
45 Years to 80 Years
Healthy volunteers
Yes
Inclusion criteria
* 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
Exclusion criteria
* 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pituitary Response to GnRH | 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 | 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 |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Younger PMW Postmenopausal women (PMW) 45-55 years old receiving the following series of treatments:
1. A single subcutaneous injection of the NAL-GLU GnRH antagonist at a dose of 150 mcg/kg.
2. GnRH doses of 25, 75, 250 and 750 ng/kg given IV every 4 hr
Participants studied at baseline (period 1) and after 1 month of transdermal estrogen 0.05 mg/day (period 2) | 10 |
| Older PMW Postmenopausal women (PMW) 70-80 years old receiving the following series of treatments:
1. A single subcutaneous injection of the NAL-GLU GnRH antagonist at a dose of 150 mcg/kg.
2. GnRH doses of 25, 75, 250 and 750 ng/kg given IV every 4 hr
Participants studied at baseline (period 1) and after 1 month of transdermal estrogen 0.05 mg/day (period 2) | 9 |
| Total | 19 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Plus Estrogen | Adverse Event | 0 | 1 |
| Plus Estrogen | Lost to Follow-up | 2 | 0 |
Baseline characteristics
| Characteristic | Younger PMW | Total | Older PMW |
|---|---|---|---|
| Age, Continuous | 52.9 years STANDARD_DEVIATION 2.46 | 61.9 years STANDARD_DEVIATION 10.6 | 72.8 years STANDARD_DEVIATION 2.88 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 3 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 7 Participants | 16 Participants | 9 Participants |
| Region of Enrollment United States | 10 participants | 19 participants | 9 participants |
| Sex: Female, Male Female | 10 Participants | 19 Participants | 9 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 9 |
| other Total, other adverse events | 2 / 10 | 0 / 9 |
| serious Total, serious adverse events | 0 / 10 | 1 / 9 |
Outcome results
Primary
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
Time frame: Peak hormone level within 2 hours post GnRH doses
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Younger PMW | Effect of Estrogen on Pituitary Response to GnRH | LH amp change: 750 ng/kg GnRH | -27.1 IU/L | Standard Error 18.8 |
| Younger PMW | Effect of Estrogen on Pituitary Response to GnRH | FSH amp change: 750 ng/kg | -15.4 IU/L | Standard Error 3.9 |
| Younger PMW | Effect of Estrogen on Pituitary Response to GnRH | FSH amp change: 75 ng/kg | -6.7 IU/L | Standard Error 7.5 |
| Younger PMW | Effect of Estrogen on Pituitary Response to GnRH | LH amp change: 25 ng/kg GnRH | -0.38 IU/L | Standard Error 1.9 |
| Younger PMW | Effect of Estrogen on Pituitary Response to GnRH | FSH amp change: 25 ng/kg GnRH | -2.7 IU/L | Standard Error 1.9 |
| Younger PMW | Effect of Estrogen on Pituitary Response to GnRH | LH amp change: 75 ng/kg GnRH | -2.9 IU/L | Standard Error 3.1 |
| Younger PMW | Effect of Estrogen on Pituitary Response to GnRH | FSH amp change: 250 ng/kg | -12.1 IU/L | Standard Error 3.3 |
| Younger PMW | Effect of Estrogen on Pituitary Response to GnRH | LH amp change: 250 ng/kg GnRH | -17.8 IU/L | Standard Error 8 |
| Older PMW | Effect of Estrogen on Pituitary Response to GnRH | FSH amp change: 250 ng/kg | -1.9 IU/L | Standard Error 2.2 |
| Older PMW | Effect of Estrogen on Pituitary Response to GnRH | LH amp change: 750 ng/kg GnRH | -14.2 IU/L | Standard Error 4.6 |
| Older PMW | Effect of Estrogen on Pituitary Response to GnRH | FSH amp change: 25 ng/kg GnRH | -0.6 IU/L | Standard Error 1.3 |
| Older PMW | Effect of Estrogen on Pituitary Response to GnRH | FSH amp change: 75 ng/kg | 0.21 IU/L | Standard Error 1.8 |
| Older PMW | Effect of Estrogen on Pituitary Response to GnRH | LH amp change: 250 ng/kg GnRH | -5.4 IU/L | Standard Error 3.4 |
| Older PMW | Effect of Estrogen on Pituitary Response to GnRH | FSH amp change: 750 ng/kg | -5.8 IU/L | Standard Error 3.3 |
| Older PMW | Effect of Estrogen on Pituitary Response to GnRH | LH amp change: 25 ng/kg GnRH | -0.53 IU/L | Standard Error 1 |
| Older PMW | Effect of Estrogen on Pituitary Response to GnRH | LH amp change: 75 ng/kg GnRH | -0.54 IU/L | Standard Error 1.7 |
p-value: <0.01Repeated measured ANCOVA
p-value: <0.0001Repeated measures ANCOVA
p-value: <0.02Repeated measures ANCOVA
p-value: =0.4Repeated measures ANCOVA
Primary
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
Time frame: Peak hormone level within 2 hours post GnRH doses
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Younger PMW | Pituitary Response to GnRH | LH % change: 250 ng/kg GnRH | 62.82 Percent change | Standard Error 12.15 |
| Younger PMW | Pituitary Response to GnRH | LH % change: 750 ng/kg GnRH | 137.51 Percent change | Standard Error 14.17 |
| Younger PMW | Pituitary Response to GnRH | FSH % change 25 ng/kg GnRH | 5.30 Percent change | Standard Error 0.88 |
| Younger PMW | Pituitary Response to GnRH | FSH % change: 75 ng/kg GnRH | 8.01 Percent change | Standard Error 1.13 |
| Younger PMW | Pituitary Response to GnRH | FSH % change: 250 ng/kg GnRH | 14.57 Percent change | Standard Error 1.87 |
| Younger PMW | Pituitary Response to GnRH | FSH % change: 750 ng/kg | 23.55 Percent change | Standard Error 1.82 |
| Younger PMW | Pituitary Response to GnRH | LH % change: 25 ng/kg GnRH | 7.88 Percent change | Standard Error 1.76 |
| Younger PMW | Pituitary Response to GnRH | LH % change: 75 ng/kg GnRH | 20.08 Percent change | Standard Error 2.94 |
| Older PMW | Pituitary Response to GnRH | LH % change: 75 ng/kg GnRH | 17.27 Percent change | Standard Error 3.65 |
| Older PMW | Pituitary Response to GnRH | LH % change: 250 ng/kg GnRH | 43.96 Percent change | Standard Error 5.7 |
| Older PMW | Pituitary Response to GnRH | FSH % change: 250 ng/kg GnRH | 9.29 Percent change | Standard Error 1.32 |
| Older PMW | Pituitary Response to GnRH | LH % change: 750 ng/kg GnRH | 103.73 Percent change | Standard Error 8.6 |
| Older PMW | Pituitary Response to GnRH | LH % change: 25 ng/kg GnRH | 6.00 Percent change | Standard Error 1.49 |
| Older PMW | Pituitary Response to GnRH | FSH % change 25 ng/kg GnRH | 4.32 Percent change | Standard Error 0.89 |
| Older PMW | Pituitary Response to GnRH | FSH % change: 750 ng/kg | 17.53 Percent change | Standard Error 2.4 |
| Older PMW | Pituitary Response to GnRH | FSH % change: 75 ng/kg GnRH | 6.98 Percent change | Standard Error 1.26 |
p-value: <0.001Repeated measures ANCOVA
Comparison: null hypothesis: there will be no difference in the LH and FSH responses to graded doses of GnRH between younger and older postmenopausal womenp-value: <0.03Repeated measures ANCOVA
p-value: <0.001Repeated measures ANCOVA
p-value: <0.005Repeated measures ANCOVA