The Effects of Aging and Estrogen on the Pituitary

• Sponsor: Massachusetts General Hospital (Other)
• Overall Status: Unknown status
• CT.gov ID: NCT00386022
• Collaborator: National Institute on Aging (NIA) (NIH)
• Enrollment: 19
• Location: 1
• Arms: 2
• Duration (Months): 192
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Healthy	Drug: GnRH; Drug: NAL-GLU GnRH antagonist; Drug: Estrogen patch	Phase 2/Phase 3

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

• Study Type: Interventional
• Actual Enrollment: 19 participants
• Allocation: Randomized
• Intervention Model: Sequential Assignment
• 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.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)
• Primary Purpose: Other
• Official Title: The Effect of Aging on the Isolated Pituitary Response to Gonadotropin Releasing Hormone at Baseline and With Low Dose Estrogen Administration
• Study Start Date: Jan 1, 2002
• Actual Primary Completion Date: Jan 1, 2012
• Anticipated Study Completion Date: Jan 1, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Young postmenopausal women intervention: graded doses of GnRH following NAL-GLU GnRH antagonist administration with or without transdermal estrogen patch	Drug: GnRH; GnRH doses of 25, 75, 250 and 750 ng/kg will be given IV every 4 hr at baseline and after transdermal estradiol; Other Names: gonadotropin-releasing hormone Factryl ; Drug: NAL-GLU GnRH antagonist; A single subcutaneous injection of the NAL-GLU GnRH antagonist at a dose of 150 mcg/kg before and after transdermal estradiol; Other Names: GnRH antagonist ; Drug: Estrogen patch; transdermal estrogen patches 0.05mg/day, changing the patch every 86 hr in second part of sequential study; Other Names: Climara Estraderm
Experimental: Older postmenopausal women intervention: graded doses of GnRH following NAL-GLU GnRH antagonist administration with or without transdermal estrogen patch	Drug: GnRH; GnRH doses of 25, 75, 250 and 750 ng/kg will be given IV every 4 hr at baseline and after transdermal estradiol; Other Names: gonadotropin-releasing hormone Factryl ; Drug: NAL-GLU GnRH antagonist; A single subcutaneous injection of the NAL-GLU GnRH antagonist at a dose of 150 mcg/kg before and after transdermal estradiol; Other Names: GnRH antagonist ; Drug: Estrogen patch; transdermal estrogen patches 0.05mg/day, changing the patch every 86 hr in second part of sequential study; Other Names: Climara Estraderm

Outcome Measures

Primary Outcome Measures

1. 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

2. 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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 45 Years to 80 Years
• Sexes Eligible for Study: Female
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Massachusetts General Hospital	Boston	Massachusetts	United States	02114

Sponsors and Collaborators

• Massachusetts General Hospital
• National Institute on Aging (NIA)

Investigators

• Principal Investigator: Janet E Hall, M.D., Massachusetts General Hospital

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Janet E. Hall, MD, Associate Physician, Massachusetts General Hospital
• ClinicalTrials.gov Identifier: NCT00386022
• Other Study ID Numbers: 2000-P-002498; R01AG013241
• First Posted: Oct 11, 2006
• Last Update Posted: Apr 13, 2017
• Last Verified: Apr 1, 2017

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by Janet E. Hall, MD, Associate Physician, Massachusetts General Hospital: Gonadotropin-releasing hormone; Estrogens; postmenopausal women; Pituitary hormones
• Additional relevant MeSH terms: Pituitary Diseases; Prolactin Release-Inhibiting Factors; Estrogens; LHRH, N-Ac-2-Nal(1)-4-Cl-Phe(2)-3-Pal(3)-Arg(5)-Glu(6)-AlaNH2(10)-

Study Results

Participant Flow

Arm/Group Title	Younger PMW	Older PMW
Arm/Group Description	Postmenopausal women (PMW) 45-55 years old receiving the following series of treatments: A single subcutaneous injection of the NAL-GLU GnRH antagonist at a dose of 150 mcg/kg. 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)	Postmenopausal women (PMW) 70-80 years old receiving the following series of treatments: A single subcutaneous injection of the NAL-GLU GnRH antagonist at a dose of 150 mcg/kg. 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)
Period Title: Baseline
STARTED	10	9
All Doses of GnRH	10	9
COMPLETED	10	9
NOT COMPLETED	0	0
Period Title: Baseline
STARTED	10	9
Estrogen Patch	8	9
All Doses GnRH	8	8
COMPLETED	8	8
NOT COMPLETED	2	1

Baseline Characteristics

Arm/Group Title	Younger PMW	Older PMW	Total
Arm/Group Description	Postmenopausal women (PMW) 45-55 years old receiving the following series of treatments: A single subcutaneous injection of the NAL-GLU GnRH antagonist at a dose of 150 mcg/kg. 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)	Postmenopausal women (PMW) 70-80 years old receiving the following series of treatments: A single subcutaneous injection of the NAL-GLU GnRH antagonist at a dose of 150 mcg/kg. 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)	Total of all reporting groups
Overall Participants	10	9	19
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	52.9 (2.46)	72.8 (2.88)	61.9 (10.6)
Sex: Female, Male (Count of Participants)
Female	10 100%	9 100%	19 100%
Male	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	3 30%	0 0%	3 15.8%
White	7 70%	9 100%	16 84.2%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	10 100%	9 100%	19 100%

Outcome Measures

1. Primary Outcome

Title	Pituitary Response to GnRH
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Younger PMW	Older PMW
Arm/Group Description	Postmenopausal women aged 45-55 years studied at baseline using the following interventions: A single subcutaneous injection of the NAL-GLU GnRH antagonist at a dose of 150 mcg/kg. GnRH doses of 25, 75, 250 and 750 ng/kg given IV every 4 hr	Postmenopausal women aged 70-80 years studied at baseline using the following interventions: A single subcutaneous injection of the NAL-GLU GnRH antagonist at a dose of 150 mcg/kg. GnRH doses of 25, 75, 250 and 750 ng/kg given IV every 4 hr
Measure Participants	10	9
LH % change: 25 ng/kg GnRH	7.88 (1.76)	6.00 (1.49)
LH % change: 75 ng/kg GnRH	20.08 (2.94)	17.27 (3.65)
LH % change: 250 ng/kg GnRH	62.82 (12.15)	43.96 (5.70)
LH % change: 750 ng/kg GnRH	137.51 (14.17)	103.73 (8.60)
FSH % change 25 ng/kg GnRH	5.30 (.88)	4.32 (.89)
FSH % change: 75 ng/kg GnRH	8.01 (1.13)	6.98 (1.26)
FSH % change: 250 ng/kg GnRH	14.57 (1.87)	9.29 (1.32)
FSH % change: 750 ng/kg	23.55 (1.82)	17.53 (2.40)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Younger PMW, Older PMW
	Comments
	Type of Statistical Test	Equivalence
	Comments	null hypothesis will be accepted if there is no difference in the LH response to GnRH as a function of dose in young or old postmenopausal women
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	LH % change with dose
	Method	Repeated measures ANCOVA
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Younger PMW, Older PMW
	Comments	null hypothesis: there will be no difference in the LH and FSH responses to graded doses of GnRH between younger and older postmenopausal women
	Type of Statistical Test	Equivalence
	Comments	null hypothesis will be accepted if there is no difference in the LH response to GnRH between younger and older postmenopausal women
Statistical Test of Hypothesis	p-Value	<0.03
	Comments	LH % change with age
	Method	Repeated measures ANCOVA
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Younger PMW, Older PMW
	Comments
	Type of Statistical Test	Equivalence
	Comments	null hypothesis will be accepted if there is no difference in the FSH response to GnRH as a function of dose in younger or older postmenopausal women
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	FSH % change with dose
	Method	Repeated measures ANCOVA
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Younger PMW, Older PMW
	Comments
	Type of Statistical Test	Equivalence
	Comments	null hypothesis will be accepted if there is no difference in the FSH response to GnRH between young and old postmenopausal women
Statistical Test of Hypothesis	p-Value	<0.005
	Comments	FSH % change with age
	Method	Repeated measures ANCOVA
	Comments

2. Primary Outcome

Title	Effect of Estrogen on Pituitary Response to GnRH
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Young Postmenopausal Women	Older Postmenopausal Women
Arm/Group Description	Postmenopausal women aged 45-55 years studied after 1 month of transdermal estrogen 0.05 mg/day using the following interventions: A single subcutaneous injection of the NAL-GLU GnRH antagonist at a dose of 150 mcg/kg. GnRH doses of 25, 75, 250 and 750 ng/kg given IV every 4 hr	Postmenopausal women aged 70-80 years studied after 1 month of transdermal estrogen 0.05 mg/day using the following interventions: A single subcutaneous injection of the NAL-GLU GnRH antagonist at a dose of 150 mcg/kg. GnRH doses of 25, 75, 250 and 750 ng/kg given IV every 4 hr
Measure Participants	8	8
LH amp change: 25 ng/kg GnRH	-0.38 (1.9)	-0.53 (1.0)
LH amp change: 75 ng/kg GnRH	-2.9 (3.1)	-0.54 (1.7)
LH amp change: 250 ng/kg GnRH	-17.8 (8.0)	-5.4 (3.4)
LH amp change: 750 ng/kg GnRH	-27.1 (18.8)	-14.2 (4.6)
FSH amp change: 25 ng/kg GnRH	-2.7 (1.9)	-0.6 (1.3)
FSH amp change: 75 ng/kg	-6.7 (7.5)	0.21 (1.8)
FSH amp change: 250 ng/kg	-12.1 (3.3)	-1.9 (2.2)
FSH amp change: 750 ng/kg	-15.4 (3.9)	-5.8 (3.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Younger PMW, Older PMW
	Comments
	Type of Statistical Test	Equivalence
	Comments	null hypothesis will be accepted if there is no effect of estrogen on the LH response to GnRH in younger and older postmenopausal women
Statistical Test of Hypothesis	p-Value	<0.01
	Comments	LH amplitude response with estrogen
	Method	Repeated measured ANCOVA
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Younger PMW, Older PMW
	Comments
	Type of Statistical Test	Equivalence
	Comments	The null hypothesis will be accepted if there is no effect of estrogen on the FSH response to GnRH in younger and older postmenopausal women
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	FSH amplitude response with estrogen
	Method	Repeated measures ANCOVA
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Younger PMW, Older PMW
	Comments
	Type of Statistical Test	Equivalence
	Comments	The null hypothesis will be accepted if there is no effect of age on the effect of estrogen on the FSH response to GnRH
Statistical Test of Hypothesis	p-Value	<0.02
	Comments	FSH amplitude response to estrogen with age
	Method	Repeated measures ANCOVA
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Younger PMW, Older PMW
	Comments
	Type of Statistical Test	Equivalence
	Comments	The null hypothesis will be accepted if there is no effect of age on the effect of estrogen on the LH response to GnRH
Statistical Test of Hypothesis	p-Value	=0.4
	Comments	LH amplitude response to estrogen with age
	Method	Repeated measures ANCOVA
	Comments

Adverse Events

Time Frame	3 months
Adverse Event Reporting Description	Information on AEs was collected for a 3 month period from study entry for each subject.
Arm/Group Title	Younger PMW		Older PMW
Arm/Group Description	Postmenopausal women aged 45-55 years studied at baseline (period 1) and after 1 month of transdermal estrogen 0.05 mg/day (period 2) using the following interventions: A single subcutaneous injection of the NAL-GLU GnRH antagonist at a dose of 150 mcg/kg. GnRH doses of 25, 75, 250 and 750 ng/kg given IV every 4 hr		Postmenopausal women aged 70-80 years studied at baseline (period 1) and after 1 month of transdermal estrogen 0.05 mg/day (period 2) using the following interventions: A single subcutaneous injection of the NAL-GLU GnRH antagonist at a dose of 150 mcg/kg. GnRH doses of 25, 75, 250 and 750 ng/kg given IV every 4 hr
All Cause Mortality
	Younger PMW		Older PMW
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/10 (0%)		0/9 (0%)
Serious Adverse Events
	Younger PMW		Older PMW
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/10 (0%)		1/9 (11.1%)
Cardiac disorders
New Onset Rapid Atrial Fibrillation	0/10 (0%)	0	1/9 (11.1%)	1
Other (Not Including Serious) Adverse Events
	Younger PMW		Older PMW
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/10 (20%)		0/9 (0%)
Infections and infestations
genital herpes diagnosis	1/10 (10%)	1	0/9 (0%)	0
Musculoskeletal and connective tissue disorders
fall	1/10 (10%)	1	0/9 (0%)	0

Limitations/Caveats

No significant limitations were present in this study and the subsequent analysis.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.