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Estrogen Sensitivity and Ovulatory Dysfunction in Obesity

Primary Purpose

Obesity, Infertility

Status
Completed
Phase
Not Applicable
Locations
United States
Study Type
Interventional
Intervention
Estradiol
Gonadotropin-releasing hormone (GnRH)
Progesterone
Sponsored by
University of Colorado, Denver
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional basic science trial for Obesity focused on measuring LH pulsatility, Obesity, Reproduction

Eligibility Criteria

18 Years - 42 Years (Adult)FemaleAccepts Healthy Volunteers

Inclusion Criteria:

  • Age 18-42 at study entry
  • Regular menstrual cycles every 25-40 days
  • BMI 18- 25 kg/m2 or ≥30kg/m2
  • Good general health
  • Prolactin and thyroid-stimulating hormone (TSH) within normal laboratory ranges at screening
  • Baseline hemoglobin >11 gm/dl.

Exclusion Criteria:

  • Positive screen for Activated Protein C resistance
  • Any contraindications to exogenous estrogen, including previous thromboembolic events or stroke, history of an estrogen-dependent tumor, active liver disease, undiagnosed abnormal uterine bleeding, hypertriglyceridemia, smoking, hypertension
  • History of chronic disease affecting hormone production, metabolism or clearance (including diabetes mellitus) or abnormal renal or liver function at screening, such as elevated aspartate or alanine aminotransferases or elevated blood urea nitrogen (BUN) or creatinine
  • Current use of thiazolidinediones or metformin (known to interact with reproductive hormones)
  • Use of hormones affecting hypothalamic-pituitary ovarian axis within three months of enrollment
  • Strenuous exercise (>4 hours per week)
  • Pregnancy, breast-feeding or current active attempts to conceive

Sites / Locations

  • University of Colorado, Anschutz Medical Campus

Arms of the Study

Arm 1

Arm 2

Arm Type

Other

Experimental

Arm Label

Group 1 - Normal Weight

Group 2 - Obese

Arm Description

Group 1: Normal weight (BMI 18-25 kg/m2) Subjects were instructed to apply 0.1 mg/d transdermal estrogen (Estradiol) for one month. Pituitary response was assessed to determine how estradiol administration altered pituitary sensitivity to Gonadotropin-releasing hormone - GnRH. Subjects who failed to initiate a menstrual period following 40 days on the patch were instructed to take 200 mg daily of progesterone for 10 days or as long as deemed necessary.

Group 2: Obese (BMI >30 kg/m2) Subjects were instructed to apply 0.1 mg/d transdermal estrogen (Estradiol) for one month. Pituitary response was assessed to determine how estradiol administration altered pituitary sensitivity to Gonadotropin-releasing hormone - GnRH. Subjects who failed to initiate a menstrual period following 40 days on the patch were instructed to take 200 mg daily of progesterone for 10 days or as long as deemed necessary.

Outcomes

Primary Outcome Measures

Luteinizing Hormone Pulse Amplitude
The study is powered on luteinizing hormone pulse amplitude because it is the clinical outcome for which the most data is available. The primary comparison is whether there is a significant reduction in the pulse amplitude in the obese between the pre- and post-treatment periods and whether there is no change in the pulse amplitude in the normal weight patients between the pre and post-treatment periods.
Luteinizing Hormone Pulse Amplitude

Secondary Outcome Measures

Full Information

First Posted
June 22, 2011
Last Updated
April 2, 2015
Sponsor
University of Colorado, Denver
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1. Study Identification

Unique Protocol Identification Number
NCT01381016
Brief Title
Estrogen Sensitivity and Ovulatory Dysfunction in Obesity
Official Title
Estrogen Sensitivity and Ovulatory Dysfunction in Obesity
Study Type
Interventional

2. Study Status

Record Verification Date
April 2015
Overall Recruitment Status
Completed
Study Start Date
June 2011 (undefined)
Primary Completion Date
January 2013 (Actual)
Study Completion Date
January 2013 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of Colorado, Denver

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
The sole purpose of this study is to evaluate pathophysiology of disease. The disease state that is being evaluated is the obesity-related alterations in reproductive hormones The obesity epidemic in the United States is advancing at an accelerated pace. It is estimated that by 2015, 41% of U.S. adults will be obese as defined by a body mass index (BMI) of greater than 30 kg/m2. The U.S. government's 2010 Dietary Guidelines regard obesity as the single greatest health hazard in this century. Female adult obesity is associated with menstrual cycle irregularities, ovulatory dysfunction and a higher risk of obstetrical complications. This reproductive phenotype of obesity is worsened by further increases in BMI and is not solely due to anovulatory infertility. While the association of adiposity with subfertility is well documented in population studies, the underlying mechanisms remain poorly understood. The main objective of this proposal is to clarify the nature of the obesity-related reproductive endocrine abnormalities and identify potential etiologies amenable to therapy. Hypothesis: The hypothalamic-pituitary axis is abnormally sensitive to estradiol negative feedback in obesity.
Detailed Description
Design: paired assessments Pre and Post estrogen administration in obese and normal weight women AIM 1: To test the pituitary and hypothalamic responsiveness in obesity, we will examine the luteinizing hormone (LH) and follicle-stimulating hormone (FSH) pulsatility during frequent blood sampling. AIM 2: To test the ovarian responsiveness in obesity, we will examine urinary reproductive hormones (E1c, estrone conjugates, and Pdg, pregnanediol glucuronide) over an entire menstrual cycle. AIM 3: To test the hypothesis that central adiposity is associated with reproductive hormone alterations in obesity, we will quantitatively assess body composition by dual energy x-ray absorptiometry (DXA).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Obesity, Infertility
Keywords
LH pulsatility, Obesity, Reproduction

7. Study Design

Primary Purpose
Basic Science
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
30 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Group 1 - Normal Weight
Arm Type
Other
Arm Description
Group 1: Normal weight (BMI 18-25 kg/m2) Subjects were instructed to apply 0.1 mg/d transdermal estrogen (Estradiol) for one month. Pituitary response was assessed to determine how estradiol administration altered pituitary sensitivity to Gonadotropin-releasing hormone - GnRH. Subjects who failed to initiate a menstrual period following 40 days on the patch were instructed to take 200 mg daily of progesterone for 10 days or as long as deemed necessary.
Arm Title
Group 2 - Obese
Arm Type
Experimental
Arm Description
Group 2: Obese (BMI >30 kg/m2) Subjects were instructed to apply 0.1 mg/d transdermal estrogen (Estradiol) for one month. Pituitary response was assessed to determine how estradiol administration altered pituitary sensitivity to Gonadotropin-releasing hormone - GnRH. Subjects who failed to initiate a menstrual period following 40 days on the patch were instructed to take 200 mg daily of progesterone for 10 days or as long as deemed necessary.
Intervention Type
Drug
Intervention Name(s)
Estradiol
Other Intervention Name(s)
Climara, transdermal estrogen
Intervention Description
Subjects were instructed to apply 0.1 mg/d transdermal estrogen for one month.
Intervention Type
Drug
Intervention Name(s)
Gonadotropin-releasing hormone (GnRH)
Other Intervention Name(s)
Lutrelef or gonadorelin acetate
Intervention Description
Pituitary response was assessed to determine how estradiol administration alters pituitary sensitivity to GnRH.
Intervention Type
Drug
Intervention Name(s)
Progesterone
Other Intervention Name(s)
Prometrium or medroxyproge sterone acetate
Intervention Description
Subjects who failed to initiate a menstrual period following 40 days on the patch were instructed to take 200 mg daily of progesterone for 10 days or as long as deemed necessary.
Primary Outcome Measure Information:
Title
Luteinizing Hormone Pulse Amplitude
Description
The study is powered on luteinizing hormone pulse amplitude because it is the clinical outcome for which the most data is available. The primary comparison is whether there is a significant reduction in the pulse amplitude in the obese between the pre- and post-treatment periods and whether there is no change in the pulse amplitude in the normal weight patients between the pre and post-treatment periods.
Time Frame
Baseline
Title
Luteinizing Hormone Pulse Amplitude
Time Frame
Post estradiol at one month

10. Eligibility

Sex
Female
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
42 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria: Age 18-42 at study entry Regular menstrual cycles every 25-40 days BMI 18- 25 kg/m2 or ≥30kg/m2 Good general health Prolactin and thyroid-stimulating hormone (TSH) within normal laboratory ranges at screening Baseline hemoglobin >11 gm/dl. Exclusion Criteria: Positive screen for Activated Protein C resistance Any contraindications to exogenous estrogen, including previous thromboembolic events or stroke, history of an estrogen-dependent tumor, active liver disease, undiagnosed abnormal uterine bleeding, hypertriglyceridemia, smoking, hypertension History of chronic disease affecting hormone production, metabolism or clearance (including diabetes mellitus) or abnormal renal or liver function at screening, such as elevated aspartate or alanine aminotransferases or elevated blood urea nitrogen (BUN) or creatinine Current use of thiazolidinediones or metformin (known to interact with reproductive hormones) Use of hormones affecting hypothalamic-pituitary ovarian axis within three months of enrollment Strenuous exercise (>4 hours per week) Pregnancy, breast-feeding or current active attempts to conceive
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Alex Polotsky, MD
Organizational Affiliation
University of Colorado, Denver
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Colorado, Anschutz Medical Campus
City
Aurora
State/Province
Colorado
ZIP/Postal Code
80045
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
17440019
Citation
Jain A, Polotsky AJ, Rochester D, Berga SL, Loucks T, Zeitlian G, Gibbs K, Polotsky HN, Feng S, Isaac B, Santoro N. Pulsatile luteinizing hormone amplitude and progesterone metabolite excretion are reduced in obese women. J Clin Endocrinol Metab. 2007 Jul;92(7):2468-73. doi: 10.1210/jc.2006-2274. Epub 2007 Apr 17.
Results Reference
background
PubMed Identifier
18829008
Citation
Rochester D, Jain A, Polotsky AJ, Polotsky H, Gibbs K, Isaac B, Zeitlian G, Hickmon C, Feng S, Santoro N. Partial recovery of luteal function after bariatric surgery in obese women. Fertil Steril. 2009 Oct;92(4):1410-1415. doi: 10.1016/j.fertnstert.2008.08.025. Epub 2008 Sep 30.
Results Reference
background
PubMed Identifier
23958434
Citation
Roth LW, Allshouse AA, Lesh J, Polotsky AJ, Santoro N. The correlation between self-reported and measured height, weight, and BMI in reproductive age women. Maturitas. 2013 Oct;76(2):185-8. doi: 10.1016/j.maturitas.2013.07.010. Epub 2013 Aug 16.
Results Reference
derived
Links:
URL
http://www.cudoctors.com/find-a-doctor/profile/?providerID=4029&name=polotsky
Description
PI Profile

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Estrogen Sensitivity and Ovulatory Dysfunction in Obesity

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