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T-IR- Study to Understand the Effects of Testosterone and Estrogen on the Body's Response to the Hormone Insulin (T-IR)

This study is ongoing, but not recruiting participants.
Sponsor:
ClinicalTrials.gov Identifier:
NCT01686828
First Posted: September 18, 2012
Last Update Posted: July 6, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Information provided by (Responsible Party):
Katya Rubinow, University of Washington
  Purpose
The purpose of this research study is to understand the effects of testosterone and estrogen on the body's response to the hormone insulin.

Condition Intervention Phase
Insulin Resistance Type 2 Diabetes Mellitus Obesity Androgen Deficiency Metabolic Disease Drug: Acyline Drug: Testosterone 1.62% gel Drug: Letrozole Drug: Placebo gel (for Testosterone 1.62% gel) Drug: Placebo pill (for Letrozole) Phase 1 Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: Androgen-mediated Pathways in the Regulation of Insulin Sensitivity in Men

Resource links provided by NLM:


Further study details as provided by Katya Rubinow, University of Washington:

Primary Outcome Measures:
  • Insulin Sensitivity Quantified by Matsuda Index [ Time Frame: 4 weeks ]
    Whole body insulin sensitivity as quantified by Matsuda Index at the end of the treatment period, calculated by the following equation: 10,000/square root of(FPG*FI)*(FPG+PG30*2+PG60*2+PG90*2+PG120)/8*(FPI+PI30*2+PI60*2+PI90*2+PI)/8). FPG=fasting plasma glucose level; FPI=fasting plasma insulin level; PG30,60,90, and 120=plasma glucose levels sampled at 30,60,90, and 120 minutes after oral glucose load; PI30,60,90, and 120=plasma insulin levels sampled at 30,60,90, and 120 minutes after the oral glucose load


Secondary Outcome Measures:
  • Changes in Body Composition [ Time Frame: 4 weeks ]
    Fat mass and lean mass were measured by dual energy X-ray absorptiometry (DEXA) at baseline and at the end of the 4 week treatment period

  • Changes in Adipose Tissue Gene Expression [ Time Frame: 4 weeks ]
    We examined whether differences in lipoprotein lipase expression would be evident across study treatment groups. RNA was isolated from whole adipose tissue gene expression, and complementary DNA (cDNA) was synthesized from 1.5 ug of RNA per sample. Gene expression was measured by polymerase chain reaction (PCR) using predesigned TaqMan® Gene Expression Assays. Standard curves were included on each plate, so Ct values were converted to copy numbers of the target gene. Expression values were normalized to the geometric mean of the housekeeping genes phosphoglycerate kinase and 18s.


Enrollment: 53
Study Start Date: June 2013
Estimated Study Completion Date: December 2017
Primary Completion Date: May 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Acyline & placebo gel & placebo pill
Acyline (300mcg/kg) + placebo transdermal gel + placebo pill daily
Drug: Acyline
300 mcg/mL administered subcutaneously (at Day 0, Week 2)
Drug: Placebo gel (for Testosterone 1.62% gel)
placebo gel manufactured to mimic Testosterone 1.62% gel
Drug: Placebo pill (for Letrozole)
Oral placebo aromatase inhibitor to mimic Letrozole 5mg/d
Experimental: Acyline & Testosterone 1.25g & placebo pill
Acyline (300mcg/kg) + Testosterone gel (1.25g) daily + placebo pill daily
Drug: Acyline
300 mcg/mL administered subcutaneously (at Day 0, Week 2)
Drug: Testosterone 1.62% gel
Transdermal Testosterone Gel (either 1.25g or 5g/d) for 4 weeks
Other Name: Androgel
Drug: Placebo pill (for Letrozole)
Oral placebo aromatase inhibitor to mimic Letrozole 5mg/d
Experimental: Acyline & Testosterone 5g & placebo pill
Acyline (300mcg/kg) + Testosterone gel (5g) daily + placebo pill daily
Drug: Acyline
300 mcg/mL administered subcutaneously (at Day 0, Week 2)
Drug: Testosterone 1.62% gel
Transdermal Testosterone Gel (either 1.25g or 5g/d) for 4 weeks
Other Name: Androgel
Drug: Placebo pill (for Letrozole)
Oral placebo aromatase inhibitor to mimic Letrozole 5mg/d
Experimental: Acyline & Testosterone & Letrozole
Acyline (300mcg/kg) + Testosterone gel (5g) daily + letrozole (5mg) daily
Drug: Acyline
300 mcg/mL administered subcutaneously (at Day 0, Week 2)
Drug: Testosterone 1.62% gel
Transdermal Testosterone Gel (either 1.25g or 5g/d) for 4 weeks
Other Name: Androgel
Drug: Letrozole
Letrozole oral aromatase inhibitor 5mg daily for 4 weeks
Other Name: Femara

Detailed Description:
The investigators will examine the effects of testosterone on insulin sensitivity and body composition in men. This study may lend greater insight into the increased risk of diabetes evident in men with low circulating levels of testosterone. Three drugs will be used in this study: acyline, given by injection; testosterone (T) gel that is applied to the skin; and letrozole, which is an oral drug that blocks the conversion of androgens (male hormones) to estrogens (female hormones). Acyline inhibits the production of luteinizing hormone (LH) and follicle stimulating hormone (FSH). When acyline stops the production of these hormones, it blocks the signal from the brain that stimulates the testicles to make testosterone. Adding testosterone to acyline will restore physiologic levels of testosterone in some study participants. One group of men will receive T gel with letrozole, an aromatase inhibitor; these men will have normal levels of testosterone but low levels of estrogen in the blood. This design will enable determination of the respective metabolic effects of testosterone and estrogen.
  Eligibility

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   25 Years to 55 Years   (Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Prostate-specific antigen (PSA) ≤ 3 ng/mL
  • Age 25-55 years
  • Ability to understand the study, study procedures and provide informed consent
  • Serum total T > 300 ng/dL
  • Normal reproductive history and exam
  • International Prostate Symptom Score (IPSS) < 11

Exclusion Criteria:

  • A history of prostate cancer including suspicious digital rectal exam (DRE) or history of highgrade prostatic intraepithelial neoplasia (PIN) on prostate biopsy
  • Invasive therapy for benign prostatic hyperplasia (BPH) in the past
  • History of acute urinary retention in the previous 3 months
  • Current or recent past use of androgenic or anti-androgenic drugs, steroids or drugs which interfere with steroid metabolism (within the last 3 months)
  • Current use of statins or glucocorticoids
  • Severe systemic illness (renal, liver, cardiac, lung disease, cancer, diabetes mellitus) or skin disease
  • A history of or current breast cancer
  • Known, untreated obstructive sleep apnea
  • Hematocrit > 50 or < 34
  • Hypersensitivity to any of the drugs used in the study
  • History of a bleeding disorder or anticoagulation
  • Participation in any other drug study within past 90 days
  • History of drug or alcohol abuse within the last 12 months
  • Weight > 280 lbs. or BMI ≥ 33
  • Desire for fertility in the next 6 months or current pregnant partner
  • Sperm concentration <14 million/ml
  • Significant, uncontrolled hypertension (BP >160/100 mmHg); subjects with well-controlled BP on medical therapy will be eligible to participate
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01686828


Locations
United States, Washington
University of Washington
Seattle, Washington, United States, 98195
Sponsors and Collaborators
University of Washington
Investigators
Study Chair: William J Bremner, MD, PhD University of Washington
Study Director: Stephanie T Page, MD, PhD University of Washington
Principal Investigator: Katya Rubinow, MD University of Washington
  More Information

Additional Information:
Publications:
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Yeap BB, Chubb SA, Hyde Z, Jamrozik K, Hankey GJ, Flicker L, Norman PE. Lower serum testosterone is independently associated with insulin resistance in non-diabetic older men: the Health In Men Study. Eur J Endocrinol. 2009 Oct;161(4):591-8. doi: 10.1530/EJE-09-0348. Epub 2009 Aug 6.
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Odegaard JI, Chawla A. Mechanisms of macrophage activation in obesity-induced insulin resistance. Nat Clin Pract Endocrinol Metab. 2008 Nov;4(11):619-26. doi: 10.1038/ncpendmet0976. Epub 2008 Oct 7. Review.
Rubinow KB, Snyder CN, Amory JK, Hoofnagle AN, Page ST. Acute testosterone deprivation reduces insulin sensitivity in men. Clin Endocrinol (Oxf). 2012 Feb;76(2):281-8. doi: 10.1111/j.1365-2265.2011.04189.x.
Ortega Martinez de Victoria E, Xu X, Koska J, Francisco AM, Scalise M, Ferrante AW Jr, Krakoff J. Macrophage content in subcutaneous adipose tissue: associations with adiposity, age, inflammatory markers, and whole-body insulin action in healthy Pima Indians. Diabetes. 2009 Feb;58(2):385-93. doi: 10.2337/db08-0536. Epub 2008 Nov 13.
Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW Jr. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest. 2003 Dec;112(12):1796-808.
Xu HZ, Li Y, Zhao YF. [Diagnosis and treatment of osteopathic parathyroid adenoma]. Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi. 2003 Nov;17(6):446-9. Chinese.
Lumeng CN, DelProposto JB, Westcott DJ, Saltiel AR. Phenotypic switching of adipose tissue macrophages with obesity is generated by spatiotemporal differences in macrophage subtypes. Diabetes. 2008 Dec;57(12):3239-46. doi: 10.2337/db08-0872. Epub 2008 Oct 1.
Rull A, Camps J, Alonso-Villaverde C, Joven J. Insulin resistance, inflammation, and obesity: role of monocyte chemoattractant protein-1 (or CCL2) in the regulation of metabolism. Mediators Inflamm. 2010;2010. pii: 326580. doi: 10.1155/2010/326580. Epub 2010 Sep 23.
Bastard JP, Maachi M, Lagathu C, Kim MJ, Caron M, Vidal H, Capeau J, Feve B. Recent advances in the relationship between obesity, inflammation, and insulin resistance. Eur Cytokine Netw. 2006 Mar;17(1):4-12. Review.
Chazenbalk G, Bertolotto C, Heneidi S, Jumabay M, Trivax B, Aronowitz J, Yoshimura K, Simmons CF, Dumesic DA, Azziz R. Novel pathway of adipogenesis through cross-talk between adipose tissue macrophages, adipose stem cells and adipocytes: evidence of cell plasticity. PLoS One. 2011 Mar 31;6(3):e17834. doi: 10.1371/journal.pone.0017834.
Gilliver SC. Sex steroids as inflammatory regulators. J Steroid Biochem Mol Biol. 2010 May 31;120(2-3):105-15. doi: 10.1016/j.jsbmb.2009.12.015. Epub 2010 Jan 4. Review.
Cunningham M, Gilkeson G. Estrogen receptors in immunity and autoimmunity. Clin Rev Allergy Immunol. 2011 Feb;40(1):66-73. doi: 10.1007/s12016-010-8203-5. Review.
Bouman A, Moes H, Heineman MJ, de Leij LF, Faas MM. The immune response during the luteal phase of the ovarian cycle: increasing sensitivity of human monocytes to endotoxin. Fertil Steril. 2001 Sep;76(3):555-9.
Lai JJ, Lai KP, Chuang KH, Chang P, Yu IC, Lin WJ, Chang C. Monocyte/macrophage androgen receptor suppresses cutaneous wound healing in mice by enhancing local TNF-alpha expression. J Clin Invest. 2009 Dec;119(12):3739-51. doi: 10.1172/JCI39335. Epub 2009 Nov 9.
Hildebrand F, Thobe BM, Hubbard WJ, Choudhry MA, Pape HC, Chaudry IH. Effects of 17beta-estradiol and flutamide on splenic macrophages and splenocytes after trauma-hemorrhage. Cytokine. 2006 Nov;36(3-4):107-14. Epub 2007 Jan 4.
Qiu Y, Yanase T, Hu H, Tanaka T, Nishi Y, Liu M, Sueishi K, Sawamura T, Nawata H. Dihydrotestosterone suppresses foam cell formation and attenuates atherosclerosis development. Endocrinology. 2010 Jul;151(7):3307-16. doi: 10.1210/en.2009-1268. Epub 2010 Apr 28.
Rettew JA, Huet-Hudson YM, Marriott I. Testosterone reduces macrophage expression in the mouse of toll-like receptor 4, a trigger for inflammation and innate immunity. Biol Reprod. 2008 Mar;78(3):432-7. Epub 2007 Nov 14.
Ribas V, Drew BG, Le JA, Soleymani T, Daraei P, Sitz D, Mohammad L, Henstridge DC, Febbraio MA, Hewitt SC, Korach KS, Bensinger SJ, Hevener AL. Myeloid-specific estrogen receptor alpha deficiency impairs metabolic homeostasis and accelerates atherosclerotic lesion development. Proc Natl Acad Sci U S A. 2011 Sep 27;108(39):16457-62. doi: 10.1073/pnas.1104533108. Epub 2011 Sep 7. Erratum in: Proc Natl Acad Sci U S A. 2012 Jan 10;109(2):645.
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Herbst KL, Anawalt BD, Amory JK, Bremner WJ. Acyline: the first study in humans of a potent, new gonadotropin-releasing hormone antagonist. J Clin Endocrinol Metab. 2002 Jul;87(7):3215-20.
Herbst KL, Coviello AD, Page S, Amory JK, Anawalt BD, Bremner WJ. A single dose of the potent gonadotropin-releasing hormone antagonist acyline suppresses gonadotropins and testosterone for 2 weeks in healthy young men. J Clin Endocrinol Metab. 2004 Dec;89(12):5959-65.
Page ST, Herbst KL, Amory JK, Coviello AD, Anawalt BD, Matsumoto AM, Bremner WJ. Testosterone administration suppresses adiponectin levels in men. J Androl. 2005 Jan-Feb;26(1):85-92.
Bhasin S, Storer TW, Berman N, Callegari C, Clevenger B, Phillips J, Bunnell TJ, Tricker R, Shirazi A, Casaburi R. The effects of supraphysiologic doses of testosterone on muscle size and strength in normal men. N Engl J Med. 1996 Jul 4;335(1):1-7.
Tricker R, Casaburi R, Storer TW, Clevenger B, Berman N, Shirazi A, Bhasin S. The effects of supraphysiological doses of testosterone on angry behavior in healthy eugonadal men--a clinical research center study. J Clin Endocrinol Metab. 1996 Oct;81(10):3754-8.
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Responsible Party: Katya Rubinow, Assistant Professor, Division of Metabolism, Endocrinology and Nutrition, University of Washington
ClinicalTrials.gov Identifier: NCT01686828     History of Changes
Other Study ID Numbers: 43007
First Submitted: September 12, 2012
First Posted: September 18, 2012
Results First Submitted: February 16, 2017
Results First Posted: June 14, 2017
Last Update Posted: July 6, 2017
Last Verified: June 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Keywords provided by Katya Rubinow, University of Washington:
insulin
androgens
insulin resistance
testosterone
estradiol
obesity

Additional relevant MeSH terms:
Diabetes Mellitus
Diabetes Mellitus, Type 2
Insulin Resistance
Metabolic Diseases
Glucose Metabolism Disorders
Endocrine System Diseases
Hyperinsulinism
Insulin, Globin Zinc
Insulin
Testosterone
Testosterone enanthate
Testosterone undecanoate
Testosterone 17 beta-cypionate
Androgens
Methyltestosterone
Letrozole
Aromatase Inhibitors
Hypoglycemic Agents
Physiological Effects of Drugs
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Anabolic Agents
Steroid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Estrogen Antagonists
Hormone Antagonists


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