Effect of Race on Gonadotropin Responses

• Sponsor: Massachusetts General Hospital (Other)
• Overall Status: Completed
• CT.gov ID: NCT00455962
• Collaborator: National Institutes of Health (NIH) (NIH), National Institute on Aging (NIA) (NIH)
• Enrollment: 23
• Location: 1
• Arms: 2
• Duration (Months): 83
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

The purpose of this study is to attempt to determine why estrogen levels are increased in African-American women as compared to Caucasian women by evaluating estrogen feedback on the brain. African-American women have increased bone mineral density, higher rates of twins, greater incidence of fibroids, and increased incidence of breast cancer below 40 years of age as compared to Caucasian women. These traits or illnesses are all believed to be estrogen-dependent. In fact, previous research has demonstrated increased estrogen levels in African-American women as compared to Caucasian women. However, the reason for these differences in estrogen levels has not been studied in humans. One possibility is that estrogen feedback on the brain differs between African-American and Caucasian women. Two small glands in the brain (hypothalamus and pituitary) respond to estrogen. The hypothalamus secretes GnRH (Gonadotropin-Releasing Hormone) that signals the pituitary to secrete the reproductive hormones, LH (Luteinizing Hormone) and FSH (Follicle Stimulating Hormone). These hormones act on the ovaries and signal the ovaries to produce estrogen and progesterone. Estrogen in the bloodstream then acts on the brain to stop this system when the blood has enough estrogen levels. This is called estrogen feedback. This study will determine whether there are differences in estrogen feedback between African-American and Caucasian women.

Condition or Disease	Intervention/Treatment	Phase
Premenopause; Healthy	Drug: Estradiol steroid infusion; Drug: Progesterone steroid infusion	Phase 1/Phase 2

Detailed Description

Several independent lines of evidence have suggested that reproductive endocrine dynamics may differ between African-American (AAW) and Caucasian (CW) women. There is an increased incidence of dizygotic twinning in African-American women and a further increase in the incidence reported in African women compared to Caucasian, Hispanic and Asian populations. While the etiology of dizygotic twinning is not well understood, an increase in its incidence may imply an alteration in the integrated control of the reproductive axis which usually favors development of a single ovulatory follicle. It is widely appreciated that the incidence of leiomyomas is increased in African-American women. Growth factors are likely to play a role in their control, but there is also ample evidence that leiomyomas are responsive to gonadal steroids, decreasing in size following the menopause and in response to hypoestrogenism caused by gonadotropin downregulation. African-American women under 40 years of age have a higher risk of breast cancer than women of all other ethnicities in that age group, again raising the question of whether there are also differences in reproductive hormone dynamics. Finally, bone density is increased in African-American women. In a cross-sectional study of 54 African-American and 39 Caucasian women between the ages of 20 and 90, Perry et al found that the increase in bone density in AAW was associated with increased serum levels of both estradiol and testosterone. Woods et al also described increased levels of estradiol, estrone and androstenedione levels in AAW compared with control women on a controlled low-fat, high-fiber diet. In contrast, a recent longitudinal cohort study has suggested that AAW have lower levels of estradiol with increasing age and BMI in comparison with CW. We have compared reproductive hormone levels in AAW and CW < 35 years old with a history of regular ovulatory cycles. Our preliminary data indicate that in comparison to age and BMI matched CW, estradiol levels are consistently elevated across the cycle in AAW in the absence of changes in LH, FSH, progesterone, inhibin A or inhibin B. These relationships suggest both altered negative and forward feedback interrelationships between FSH and LH and estradiol in the setting of normal inhibin levels. In the current protocol we will seek to understand the mechanisms underlying these feedback differences, which have never been addressed in these populations.

A graded infusion of estradiol and progesterone can be used to assess differences in negative and positive feedback of gonadal steroids on LH and FSH. We have hypothesized that differences exist in feedback regulation of the hypothalamus and pituitary as a function of African-American or Caucasian race in reproductive aged women.

Study Design

• Study Type: Interventional
• Actual Enrollment: 23 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Comparisons will be made between response to estradiol and progesterone infusion in young African-American and Caucasian women.Comparisons will be made between response to estradiol and progesterone infusion in young African-American and Caucasian women.
• Masking: None (Open Label)
• Masking Description: No masking.
• Primary Purpose: Other
• Official Title: Effect of Race on Gonadotropin Responses to Short Term Negative and Positive Feedback Effects of Gonadal Steroids
• Study Start Date: Jan 1, 2005
• Actual Primary Completion Date: Dec 1, 2011
• Actual Study Completion Date: Dec 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: African American women 18-35 yo intervention: estradiol steroid infusion and progesterone steroid infusion	Drug: Estradiol steroid infusion; Estradiol infusion of 0.1 mcg/kg/hr for 12 hr, 0.135 mcg/kg/hr for 12 hr, 0.165 mcg/kg/hr for 12 hr and 0.2 mcg/kg/hr for 60 hr; Other Names: E2 ; Drug: Progesterone steroid infusion; Progesterone infusion of 4.77 nmol/kg/hr (1.5 mcg/kg/hr) for 24 hr and 6.36 nmol/kg/hr (2 mcg/kg/hr) for the final 24 hr; Other Names: P
Active Comparator: Caucasian women 18-35 yo intervention: estradiol steroid infusion intervention: progesterone steroid infusion	Drug: Estradiol steroid infusion; Estradiol infusion of 0.1 mcg/kg/hr for 12 hr, 0.135 mcg/kg/hr for 12 hr, 0.165 mcg/kg/hr for 12 hr and 0.2 mcg/kg/hr for 60 hr; Other Names: E2 ; Drug: Progesterone steroid infusion; Progesterone infusion of 4.77 nmol/kg/hr (1.5 mcg/kg/hr) for 24 hr and 6.36 nmol/kg/hr (2 mcg/kg/hr) for the final 24 hr; Other Names: P

Outcome Measures

Primary Outcome Measures

1. LH Peak in Response to Estrogen Positive Feedback [5 days of estradiol and progesterone infusion]

   Estradiol levels are consistently higher in African-American vs Caucasian women across the menstrual cycle. This study was designed to determine if African-American women are more sensitive to estrogen positive feedback to generate the preovulatory LH surge using a controlled estrogen infusion paradigm.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 35 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• African-American women aged 18 to 35 years and Caucasian women aged 18 to 36 years. Subjects will be asked to volunteer information on ethnicity (self classification). Only African-American and Caucasian subjects will be included in this aim to address the specific hypotheses.

• BMI <30

• In good general health with normal TSH, prolactin and hemoglobin

• Normal BUN and Creatinine (< 2 times the upper limit of normal)

• On no medications for > 2 months before the study

• Regular menstrual cycles every 25 to 35 days and ovulation documented by a luteal phase progesterone > 3 ng/ml

• Willing to use abstinence or barrier methods of contraception for the duration of the study.

Exclusion criteria:

• postmenopausal

• smoking >9 cigarettes per day

• evidence of androgen excess.

• sensitivity to any medications used in the relevant protocol

• race other than African-American or Caucasian

• Hispanic ethnicity

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 Institutes of Health (NIH)
• 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, Clinical Associate in Medicine, Massachusetts General Hospital
• ClinicalTrials.gov Identifier: NCT00455962
• Other Study ID Numbers: 2003P-001397; Sundry Department Fund; R01AG013241
• First Posted: Apr 4, 2007
• Last Update Posted: Jul 27, 2017
• Last Verified: Jun 1, 2017

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Janet E. Hall, MD, Clinical Associate in Medicine, Massachusetts General Hospital: estrogen; progesterone; African-American; Caucasian; infusion; gonadotropins; healthy
• Additional relevant MeSH terms: Estradiol; Progesterone

Study Results

Participant Flow

Arm/Group Title	African American Women	Caucasian Women
Arm/Group Description	Healthy African-American women 18-35 years old Estradiol steroid infusion: Estradiol infusion of 0.1 mcg/kg/hr for 12 hr, 0.135 mcg/kg/hr for 12 hr, 0.165 mcg/kg/hr for 12 hr and 0.2 mcg/kg/hr for 60 hr Progesterone steroid infusion: Progesterone infusion of 4.77 nmol/kg/hr (1.5 mcg/kg/hr) for 24 hr and 6.36 nmol/kg/hr (2 mcg/kg/hr) for the final 24 hr	Healthy Caucasian women 18-35 years old Estradiol steroid infusion: Estradiol infusion of 0.1 mcg/kg/hr for 12 hr, 0.135 mcg/kg/hr for 12 hr, 0.165 mcg/kg/hr for 12 hr and 0.2 mcg/kg/hr for 60 hr Progesterone steroid infusion: Progesterone infusion of 4.77 nmol/kg/hr (1.5 mcg/kg/hr) for 24 hr and 6.36 nmol/kg/hr (2 mcg/kg/hr) for the final 24 hr
Period Title: Overall Study
STARTED	10	13
COMPLETED	10	13
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	African American Women	Caucasian Women	Total
Arm/Group Description	Healthy African-American women 18-35 years old Estradiol steroid infusion: Estradiol infusion of 0.1 mcg/kg/hr for 12 hr, 0.135 mcg/kg/hr for 12 hr, 0.165 mcg/kg/hr for 12 hr and 0.2 mcg/kg/hr for 60 hr Progesterone steroid infusion: Progesterone infusion of 4.77 nmol/kg/hr (1.5 mcg/kg/hr) for 24 hr and 6.36 nmol/kg/hr (2 mcg/kg/hr) for the final 24 hr	Healthy Caucasian women 18-35 years old Estradiol steroid infusion: Estradiol infusion of 0.1 mcg/kg/hr for 12 hr, 0.135 mcg/kg/hr for 12 hr, 0.165 mcg/kg/hr for 12 hr and 0.2 mcg/kg/hr for 60 hr Progesterone steroid infusion: Progesterone infusion of 4.77 nmol/kg/hr (1.5 mcg/kg/hr) for 24 hr and 6.36 nmol/kg/hr (2 mcg/kg/hr) for the final 24 hr	Total of all reporting groups
Overall Participants	10	13	23
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	28	28	28
Sex: Female, Male (Count of Participants)
Female	10 100%	13 100%	23 100%
Male	0 0%	0 0%	0 0%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%
Not Hispanic or Latino	10 100%	13 100%	23 100%
Unknown or Not Reported	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	10 100%	0 0%	10 43.5%
White	0 0%	13 100%	13 56.5%
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%	13 100%	23 100%

Outcome Measures

1. Primary Outcome

Title	LH Peak in Response to Estrogen Positive Feedback
Description	Estradiol levels are consistently higher in African-American vs Caucasian women across the menstrual cycle. This study was designed to determine if African-American women are more sensitive to estrogen positive feedback to generate the preovulatory LH surge using a controlled estrogen infusion paradigm.
Time Frame	5 days of estradiol and progesterone infusion

Outcome Measure Data

Analysis Population Description

Healthy African-American and Caucasian women aged 18-35 with regular ovulatory menstrual cycles.

Arm/Group Title	African American Women	Caucasian Women
Arm/Group Description	Healthy African-American women 18-35 years old Estradiol steroid infusion: Estradiol infusion of 0.1 mcg/kg/hr for 12 hr, 0.135 mcg/kg/hr for 12 hr, 0.165 mcg/kg/hr for 12 hr and 0.2 mcg/kg/hr for 60 hr Progesterone steroid infusion: Progesterone infusion of 4.77 nmol/kg/hr (1.5 mcg/kg/hr) for 24 hr and 6.36 nmol/kg/hr (2 mcg/kg/hr) for the final 24 hr	Healthy Caucasian women 18-35 years old Estradiol steroid infusion: Estradiol infusion of 0.1 mcg/kg/hr for 12 hr, 0.135 mcg/kg/hr for 12 hr, 0.165 mcg/kg/hr for 12 hr and 0.2 mcg/kg/hr for 60 hr Progesterone steroid infusion: Progesterone infusion of 4.77 nmol/kg/hr (1.5 mcg/kg/hr) for 24 hr and 6.36 nmol/kg/hr (2 mcg/kg/hr) for the final 24 hr
Measure Participants	10	13
Mean (Standard Error) [IU/L]	80.3 (13.3)	73.1 (11.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	African American Women, Caucasian Women
	Comments	Using previously collected data from a group of 18 predominantly Caucasian women undergoing a similar infusion we determined that 22 women would be necessary to identify a 30% difference in peak LH levels, the primary outcome measure, between AAW and CW with 80% power at a significance level of 0.05.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.69
	Comments
	Method	t-test, 2 sided
	Comments

Adverse Events

Time Frame	2 years
Arm/Group Title	African American Women		Caucasian Women
Arm/Group Description	Healthy African-American women 18-35 years old Estradiol steroid infusion: Estradiol infusion of 0.1 mcg/kg/hr for 12 hr, 0.135 mcg/kg/hr for 12 hr, 0.165 mcg/kg/hr for 12 hr and 0.2 mcg/kg/hr for 60 hr Progesterone steroid infusion: Progesterone infusion of 4.77 nmol/kg/hr (1.5 mcg/kg/hr) for 24 hr and 6.36 nmol/kg/hr (2 mcg/kg/hr) for the final 24 hr		Healthy Caucasian women 18-35 years old Estradiol steroid infusion: Estradiol infusion of 0.1 mcg/kg/hr for 12 hr, 0.135 mcg/kg/hr for 12 hr, 0.165 mcg/kg/hr for 12 hr and 0.2 mcg/kg/hr for 60 hr Progesterone steroid infusion: Progesterone infusion of 4.77 nmol/kg/hr (1.5 mcg/kg/hr) for 24 hr and 6.36 nmol/kg/hr (2 mcg/kg/hr) for the final 24 hr
All Cause Mortality
	African American Women		Caucasian Women
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/18 (0%)		0/22 (0%)
Serious Adverse Events
	African American Women		Caucasian Women
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/18 (0%)		0/22 (0%)
Other (Not Including Serious) Adverse Events
	African American Women		Caucasian Women
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/18 (0%)		0/22 (0%)

Limitations/Caveats

[Not Specified]

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.