Estrogen Sensitivity and Ovulatory Dysfunction in Obesity

NCT01381016 | Completed Results

• 1 other identifier: 11-0293
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

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.

Conditions

Obesity; Infertility

Keywords

LH pulsatility; Obesity; Reproduction

Outcome Measures

Primary Outcomes (2)

• 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.

  Baseline

• Luteinizing Hormone Pulse Amplitude

  Post estradiol at one month

Study Arms (2)

Group 1 - Normal Weight

OTHER

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; Drug: Gonadotropin-releasing hormone (GnRH); Drug: Progesterone

Group 2 - Obese

EXPERIMENTAL

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; Drug: Gonadotropin-releasing hormone (GnRH); Drug: Progesterone

Interventions

Estradiol DRUG

Subjects were instructed to apply 0.1 mg/d transdermal estrogen for one month.

Also known as: Climara, transdermal estrogen

Group 1 - Normal Weight; Group 2 - Obese

Gonadotropin-releasing hormone (GnRH) DRUG

Pituitary response was assessed to determine how estradiol administration alters pituitary sensitivity to GnRH.

Also known as: Lutrelef or gonadorelin acetate

Group 1 - Normal Weight; Group 2 - Obese

Progesterone DRUG

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.

Also known as: Prometrium or medroxyproge sterone acetate

Group 1 - Normal Weight; Group 2 - Obese

Eligibility Criteria

• Age: 18 Years - 42 Years
• Sex: female
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• University of Colorado, Denver: lead

Study Sites (1)

University of Colorado, Anschutz Medical Campus

Aurora, Colorado, 80045, United States

Location

Related Publications (3)

• 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.

  PMID: 17440019 BACKGROUND

• 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.

  PMID: 18829008 BACKGROUND

• 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.

  PMID: 23958434 DERIVED

MeSH Terms

Conditions

Obesity; Infertility

Interventions

Estradiol; Gonadotropin-Releasing Hormone; Progesterone

Condition Hierarchy (Ancestors)

Overweight; Overnutrition; Nutrition Disorders; Nutritional and Metabolic Diseases; Body Weight; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Genital Diseases; Urogenital Diseases

Intervention Hierarchy (Ancestors)

Estrenes; Estranes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Estradiol Congeners; Gonadal Steroid Hormones; Gonadal Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Pituitary Hormone-Releasing Hormones; Hypothalamic Hormones; Peptide Hormones; Neuropeptides; Peptides; Amino Acids, Peptides, and Proteins; Oligopeptides; Nerve Tissue Proteins; Proteins; Pregnenediones; Pregnenes; Pregnanes; Corpus Luteum Hormones; Progesterone Congeners

Results Point of Contact

• Title: Associate Professor
• Organization: University of Colorado Denver

alex.polotsky@ucdenver.edu

(303) 724-2037

Study Officials

• Alex Polotsky, MD

  University of Colorado, Denver

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 22, 2011
• First Posted: June 27, 2011
• Study Start: June 1, 2011
• Primary Completion: January 1, 2013
• Study Completion: January 1, 2013
• Last Updated: April 20, 2015
• Results First Posted: February 18, 2015

Record last verified: 2015-04

Locations

US (1)