Estrogen Sensitivity and Ovulatory Dysfunction in Obesity

• Sponsor: University of Colorado, Denver (Other)
• Overall Status: Completed
• CT.gov ID: NCT01381016
• Collaborator: (none)
• Enrollment: 30
• Location: 1
• Arms: 2
• Duration (Months): 19.1
• Patients Per Site Per Month: 1.6

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Obesity; Infertility	Drug: Estradiol; Drug: Gonadotropin-releasing hormone (GnRH); Drug: Progesterone	N/A

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).

Study Design

• Study Type: Interventional
• Actual Enrollment: 30 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Basic Science
• Official Title: Estrogen Sensitivity and Ovulatory Dysfunction in Obesity
• Study Start Date: Jun 1, 2011
• Actual Primary Completion Date: Jan 1, 2013
• Actual Study Completion Date: Jan 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Other: Group 1 - Normal Weight 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.	Drug: Estradiol; Subjects were instructed to apply 0.1 mg/d transdermal estrogen for one month.; Other Names: Climara, transdermal estrogen ; Drug: Gonadotropin-releasing hormone (GnRH); Pituitary response was assessed to determine how estradiol administration alters pituitary sensitivity to GnRH.; Other Names: Lutrelef or gonadorelin acetate ; Drug: Progesterone; 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.; Other Names: Prometrium or medroxyproge sterone acetate
Experimental: Group 2 - Obese 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.	Drug: Estradiol; Subjects were instructed to apply 0.1 mg/d transdermal estrogen for one month.; Other Names: Climara, transdermal estrogen ; Drug: Gonadotropin-releasing hormone (GnRH); Pituitary response was assessed to determine how estradiol administration alters pituitary sensitivity to GnRH.; Other Names: Lutrelef or gonadorelin acetate ; Drug: Progesterone; 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.; Other Names: Prometrium or medroxyproge sterone acetate

Outcome Measures

Primary Outcome Measures

1. Luteinizing Hormone Pulse Amplitude [Baseline]

   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.

2. Luteinizing Hormone Pulse Amplitude [Post estradiol at one month]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 42 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: Yes

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Colorado, Anschutz Medical Campus	Aurora	Colorado	United States	80045

Sponsors and Collaborators

• University of Colorado, Denver

Investigators

• Principal Investigator: Alex Polotsky, MD, University of Colorado, Denver

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• PI Profile

Publications

• 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. Epub 2007 Apr 17.
• 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.

• Responsible Party: University of Colorado, Denver
• ClinicalTrials.gov Identifier: NCT01381016
• Other Study ID Numbers: 11-0293
• First Posted: Jun 27, 2011
• Last Update Posted: Apr 20, 2015
• Last Verified: Apr 1, 2015

• Keywords provided by University of Colorado, Denver: LH pulsatility; Obesity; Reproduction
• Additional relevant MeSH terms: Infertility; Obesity; Hormones; Estradiol; Progesterone; Estrogens

Study Results

Participant Flow

Arm/Group Title	Control	Experimental
Arm/Group Description	Group 1 "Control": Normal weight (BMI 18-25 kg/m2) Estradiol, Lutrelef or gonadorelin	Group 2 "Experimental": Obese (BMI >30 kg/m2) Estradiol, Lutrelef or gonadorelin
Period Title: Overall Study
STARTED	13	17
COMPLETED	10	11
NOT COMPLETED	3	6

Baseline Characteristics

Arm/Group Title	Control	Experimental	Total
Arm/Group Description	Group 1 "Control": Normal weight (BMI 18-25 kg/m2) Estradiol, Lutrelef or gonadorelin	Group 2 "Experimental": Obese (BMI >30 kg/m2) Estradiol, Lutrelef or gonadorelin	Total of all reporting groups
Overall Participants	13	17	30
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	13 100%	17 100%	30 100%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	29	31.76	30.57
Sex: Female, Male (Count of Participants)
Female	13 100%	17 100%	30 100%
Male	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	13 100%	17 100%	30 100%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Group 1 - Normal Weight	Group 2 - Obese
Arm/Group Description	Group 1: Normal weight (BMI 18-25 kg/m2) Estradiol, Lutrelef or gonadorelin	Group 2: Obese (BMI >30 kg/m2) Estradiol, Lutrelef or gonadorelin
Measure Participants	10	11
Mean (Standard Error) [IU/L]	2.73 (.46)	1.12 (.19)

2. Primary Outcome

Title	Luteinizing Hormone Pulse Amplitude
Time Frame	Post estradiol at one month

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Control	Experimental
Arm/Group Description	Group 1: Normal weight (BMI 18-25 kg/m2) Estradiol, Lutrelef or gonadorelin	Group 2: Obese (BMI >30 kg/m2) Estradiol, Lutrelef or gonadorelin
Measure Participants	10	11
Mean (Standard Error) [IU/L]	2.18 (.4)	1.59 (.29)

Adverse Events

Adverse Event Reporting Description	2/13 subjects enrolled as controls were considered screen failures, thus only 11 subjects were considered participants "at risk" in the control group. 2/17 subjects enrolled in experimental group were considered screen failures, thus only 15 subjects were considered participants "at risk" in the experimental group.
Arm/Group Title	Control		Experimental
Arm/Group Description	Group 1 "Control": Normal weight (BMI 18-25 kg/m2) Estradiol, Lutrelef or gonadorelin		Group 2 "Experimental": Obese (BMI >30 kg/m2) Estradiol, Lutrelef or gonadorelin
All Cause Mortality
	Control		Experimental
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Control		Experimental
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/11 (0%)		1/15 (6.7%)
Pregnancy, puerperium and perinatal conditions
Pregnancy	0/11 (0%)	0	1/15 (6.7%)	1
Other (Not Including Serious) Adverse Events
	Control		Experimental
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/11 (0%)		0/15 (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.