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

NCT01686828 | Completed Phase 1 Results DMC

• 1 other identifier: STUDY00002641
• Study Type: interventional
• Target: 53
• Locations: 1 country
• Sites: 1

Brief Summary

The purpose of this research study is to understand the effects of testosterone and estrogen on the body's response to the hormone insulin.

Conditions

Insulin Resistance; Type 2 Diabetes Mellitus; Obesity; Androgen Deficiency; Metabolic Disease

Keywords

insulin; androgens; insulin resistance; testosterone; estradiol; obesity

Outcome Measures

Primary Outcomes (1)

• Insulin Sensitivity Quantified by Matsuda Index

  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

  4 weeks

Secondary Outcomes (2)

• Changes in Body Composition

  4 weeks

• Changes in Adipose Tissue Gene Expression

  4 weeks

Study Arms (4)

Acyline & placebo gel & placebo pill

EXPERIMENTAL

Acyline (300mcg/kg) + placebo transdermal gel + placebo pill daily

Drug: Acyline; Drug: Placebo gel (for Testosterone 1.62% gel); Drug: Placebo pill (for Letrozole)

Acyline & Testosterone 1.25g & placebo pill

EXPERIMENTAL

Acyline (300mcg/kg) + Testosterone gel (1.25g) daily + placebo pill daily

Drug: Acyline; Drug: Testosterone 1.62% gel; Drug: Placebo pill (for Letrozole)

Acyline & Testosterone 5g & placebo pill

EXPERIMENTAL

Acyline (300mcg/kg) + Testosterone gel (5g) daily + placebo pill daily

Drug: Acyline; Drug: Testosterone 1.62% gel; Drug: Placebo pill (for Letrozole)

Acyline & Testosterone & Letrozole

EXPERIMENTAL

Acyline (300mcg/kg) + Testosterone gel (5g) daily + letrozole (5mg) daily

Drug: Acyline; Drug: Testosterone 1.62% gel; Drug: Letrozole

Interventions

Acyline DRUG

300 mcg/mL administered subcutaneously (at Day 0, Week 2)

Acyline & Testosterone & Letrozole; Acyline & Testosterone 1.25g & placebo pill; Acyline & Testosterone 5g & placebo pill; Acyline & placebo gel & placebo pill

Testosterone 1.62% gel DRUG

Transdermal Testosterone Gel (either 1.25g or 5g/d) for 4 weeks

Also known as: Androgel

Acyline & Testosterone & Letrozole; Acyline & Testosterone 1.25g & placebo pill; Acyline & Testosterone 5g & placebo pill

Letrozole DRUG

Letrozole oral aromatase inhibitor 5mg daily for 4 weeks

Also known as: Femara

Acyline & Testosterone & Letrozole

Placebo gel (for Testosterone 1.62% gel) DRUG

placebo gel manufactured to mimic Testosterone 1.62% gel

Acyline & placebo gel & placebo pill

Placebo pill (for Letrozole) DRUG

Oral placebo aromatase inhibitor to mimic Letrozole 5mg/d

Acyline & Testosterone 1.25g & placebo pill; Acyline & Testosterone 5g & placebo pill; Acyline & placebo gel & placebo pill

Eligibility Criteria

• Age: 25 Years - 55 Years
• Sex: male
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• University of Washington: lead

Study Sites (1)

University of Washington

Seattle, Washington, 98195, United States

Location

Related Publications (42)

• Flegal KM. Excess deaths associated with obesity: cause and effect. Int J Obes (Lond). 2006 Aug;30(8):1171-2. doi: 10.1038/sj.ijo.0803313. No abstract available.

  PMID: 16871273 BACKGROUND

• Araujo AB, O'Donnell AB, Brambilla DJ, Simpson WB, Longcope C, Matsumoto AM, McKinlay JB. Prevalence and incidence of androgen deficiency in middle-aged and older men: estimates from the Massachusetts Male Aging Study. J Clin Endocrinol Metab. 2004 Dec;89(12):5920-6. doi: 10.1210/jc.2003-031719.

  PMID: 15579737 BACKGROUND

• 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.

  PMID: 19661128 BACKGROUND

• Muller M, Grobbee DE, den Tonkelaar I, Lamberts SW, van der Schouw YT. Endogenous sex hormones and metabolic syndrome in aging men. J Clin Endocrinol Metab. 2005 May;90(5):2618-23. doi: 10.1210/jc.2004-1158. Epub 2005 Feb 1.

  PMID: 15687322 BACKGROUND

• Li C, Ford ES, Li B, Giles WH, Liu S. Association of testosterone and sex hormone-binding globulin with metabolic syndrome and insulin resistance in men. Diabetes Care. 2010 Jul;33(7):1618-24. doi: 10.2337/dc09-1788. Epub 2010 Apr 5.

  PMID: 20368409 BACKGROUND

• Smith MR, Lee H, Fallon MA, Nathan DM. Adipocytokines, obesity, and insulin resistance during combined androgen blockade for prostate cancer. Urology. 2008 Feb;71(2):318-22. doi: 10.1016/j.urology.2007.08.035.

  PMID: 18308111 BACKGROUND

• Smith MR, Lee H, Nathan DM. Insulin sensitivity during combined androgen blockade for prostate cancer. J Clin Endocrinol Metab. 2006 Apr;91(4):1305-8. doi: 10.1210/jc.2005-2507. Epub 2006 Jan 24.

  PMID: 16434464 BACKGROUND

• Mauras N, Hayes V, Welch S, Rini A, Helgeson K, Dokler M, Veldhuis JD, Urban RJ. Testosterone deficiency in young men: marked alterations in whole body protein kinetics, strength, and adiposity. J Clin Endocrinol Metab. 1998 Jun;83(6):1886-92. doi: 10.1210/jcem.83.6.4892.

  PMID: 9626114 BACKGROUND

• Yialamas MA, Dwyer AA, Hanley E, Lee H, Pitteloud N, Hayes FJ. Acute sex steroid withdrawal reduces insulin sensitivity in healthy men with idiopathic hypogonadotropic hypogonadism. J Clin Endocrinol Metab. 2007 Nov;92(11):4254-9. doi: 10.1210/jc.2007-0454. Epub 2007 Aug 28.

  PMID: 17726076 BACKGROUND

• Klimcakova E, Roussel B, Kovacova Z, Kovacikova M, Siklova-Vitkova M, Combes M, Hejnova J, Decaunes P, Maoret JJ, Vedral T, Viguerie N, Bourlier V, Bouloumie A, Stich V, Langin D. Macrophage gene expression is related to obesity and the metabolic syndrome in human subcutaneous fat as well as in visceral fat. Diabetologia. 2011 Apr;54(4):876-87. doi: 10.1007/s00125-010-2014-3. Epub 2011 Jan 26.

  PMID: 21267541 BACKGROUND

• 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.

  PMID: 18838972 BACKGROUND

• 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.

  PMID: 21797916 BACKGROUND

• 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.

  PMID: 19008342 BACKGROUND

• 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. doi: 10.1172/JCI19246.

  PMID: 14679176 BACKGROUND

• 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.

  PMID: 14663938 BACKGROUND

• 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.

  PMID: 18829989 BACKGROUND

• 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;2010:326580. doi: 10.1155/2010/326580. Epub 2010 Sep 23.

  PMID: 20936118 BACKGROUND

• 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.

  PMID: 16613757 BACKGROUND

• 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.

  PMID: 21483855 BACKGROUND

• 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.

  PMID: 20045727 BACKGROUND

• 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.

  PMID: 20352526 BACKGROUND

• 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. doi: 10.1016/s0015-0282(01)01971-9.

  PMID: 11532481 BACKGROUND

• 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.

  PMID: 19907077 BACKGROUND

• 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. doi: 10.1016/j.cyto.2006.11.002. Epub 2007 Jan 4.

  PMID: 17207634 BACKGROUND

• 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.

  PMID: 20427482 BACKGROUND

• 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. doi: 10.1095/biolreprod.107.063545. Epub 2007 Nov 14.

  PMID: 18003947 BACKGROUND

• 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.

  PMID: 21900603 BACKGROUND

• Kratz M, Purnell JQ, Breen PA, Thomas KK, Utzschneider KM, Carr DB, Kahn SE, Hughes JP, Rutledge EA, Van Yserloo B, Yukawa M, Weigle DS. Reduced adipogenic gene expression in thigh adipose tissue precedes human immunodeficiency virus-associated lipoatrophy. J Clin Endocrinol Metab. 2008 Mar;93(3):959-66. doi: 10.1210/jc.2007-0197. Epub 2007 Dec 18.

  PMID: 18089690 BACKGROUND

• 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. doi: 10.1210/jcem.87.7.8675.

  PMID: 12107227 BACKGROUND

• 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. doi: 10.1210/jc.2003-032123.

  PMID: 15579744 BACKGROUND

• 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.

  PMID: 15611571 BACKGROUND

• 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. doi: 10.1056/NEJM199607043350101.

  PMID: 8637535 BACKGROUND

• 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. doi: 10.1210/jcem.81.10.8855834.

  PMID: 8855834 BACKGROUND

• Bhasin S, Woodhouse L, Casaburi R, Singh AB, Mac RP, Lee M, Yarasheski KE, Sinha-Hikim I, Dzekov C, Dzekov J, Magliano L, Storer TW. Older men are as responsive as young men to the anabolic effects of graded doses of testosterone on the skeletal muscle. J Clin Endocrinol Metab. 2005 Feb;90(2):678-88. doi: 10.1210/jc.2004-1184. Epub 2004 Nov 23.

  PMID: 15562020 BACKGROUND

• Cuzick J, DeCensi A, Arun B, Brown PH, Castiglione M, Dunn B, Forbes JF, Glaus A, Howell A, von Minckwitz G, Vogel V, Zwierzina H. Preventive therapy for breast cancer: a consensus statement. Lancet Oncol. 2011 May;12(5):496-503. doi: 10.1016/S1470-2045(11)70030-4.

  PMID: 21441069 BACKGROUND

• Leder BZ, LeBlanc KM, Schoenfeld DA, Eastell R, Finkelstein JS. Differential effects of androgens and estrogens on bone turnover in normal men. J Clin Endocrinol Metab. 2003 Jan;88(1):204-10. doi: 10.1210/jc.2002-021036.

  PMID: 12519853 BACKGROUND

• Belgorosky A, Guercio G, Pepe C, Saraco N, Rivarola MA. Genetic and clinical spectrum of aromatase deficiency in infancy, childhood and adolescence. Horm Res. 2009;72(6):321-30. doi: 10.1159/000249159. Epub 2009 Oct 21.

  PMID: 19844120 BACKGROUND

• Campbell KL, Makar KW, Kratz M, Foster-Schubert KE, McTiernan A, Ulrich CM. A pilot study of sampling subcutaneous adipose tissue to examine biomarkers of cancer risk. Cancer Prev Res (Phila). 2009 Jan;2(1):37-42. doi: 10.1158/1940-6207.CAPR-08-0073.

  PMID: 19139016 BACKGROUND

• Muniyappa R, Lee S, Chen H, Quon MJ. Current approaches for assessing insulin sensitivity and resistance in vivo: advantages, limitations, and appropriate usage. Am J Physiol Endocrinol Metab. 2008 Jan;294(1):E15-26. doi: 10.1152/ajpendo.00645.2007. Epub 2007 Oct 23.

  PMID: 17957034 BACKGROUND

• Olefsky JM, Glass CK. Macrophages, inflammation, and insulin resistance. Annu Rev Physiol. 2010;72:219-46. doi: 10.1146/annurev-physiol-021909-135846.

  PMID: 20148674 BACKGROUND

• Rubinow KB, Vaisar T, Chao JH, Heinecke JW, Page ST. Sex steroids mediate discrete effects on HDL cholesterol efflux capacity and particle concentration in healthy men. J Clin Lipidol. 2018 Jul-Aug;12(4):1072-1082. doi: 10.1016/j.jacl.2018.04.013. Epub 2018 Apr 30.

  PMID: 29793828 DERIVED

• Chao J, Rubinow KB, Kratz M, Amory JK, Matsumoto AM, Page ST. Short-Term Estrogen Withdrawal Increases Adiposity in Healthy Men. J Clin Endocrinol Metab. 2016 Oct;101(10):3724-3731. doi: 10.1210/jc.2016-1482. Epub 2016 Aug 2.

  PMID: 27482750 DERIVED

MeSH Terms

Conditions

Insulin Resistance; Diabetes Mellitus, Type 2; Obesity; Metabolic Diseases

Interventions

acyline; Testosterone; Gels; Letrozole

Condition Hierarchy (Ancestors)

Hyperinsulinism; Glucose Metabolism Disorders; Nutritional and Metabolic Diseases; Diabetes Mellitus; Endocrine System Diseases; Overweight; Overnutrition; Nutrition Disorders; Body Weight; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Androstenols; Androstenes; Androstanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Testosterone Congeners; Gonadal Steroid Hormones; Gonadal Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Colloids; Complex Mixtures; Dosage Forms; Pharmaceutical Preparations; Nitriles; Organic Chemicals; Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Dr. Katya Rubinow
• Organization: University of Washington

rubinow@uw.edu

206-7543-3470

Study Officials

• William J Bremner, MD, PhD

  University of Washington

  STUDY CHAIR

• Stephanie T Page, MD, PhD

  University of Washington

  STUDY DIRECTOR

• Katya Rubinow, MD

  University of Washington

  PRINCIPAL INVESTIGATOR

Publication Agreements

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

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor, Division of Metabolism, Endocrinology and Nutrition

Study Record Dates

• First Submitted: September 12, 2012
• First Posted: September 18, 2012
• Study Start: June 1, 2013
• Primary Completion: May 1, 2015
• Study Completion: December 1, 2017
• Last Updated: May 8, 2018
• Results First Posted: June 14, 2017

Record last verified: 2018-04

Locations

US (1)