CEP-1 Hormonal Regulation of Circulating Endothelial Progenitor Cells and HDL-C in Men

NCT00729859 | Completed Phase 2 Results

• 2 other identifiers: 33853-AU54HD042454
• Study Type: interventional
• Target: 31
• Locations: 0 countries
• Sites: N/A

Brief Summary

The original purpose of this research study was to understand the effects of testosterone (T) and estrogen on stem cells in the blood. The knowledge would be used to help understand the effects of T and estrogen on cardiovascular (heart and blood vessel) disease, and to help in the development of a safe male hormonal contraceptive. The effect of androgens on the number of circulating endothelial progenitor (CEP) cells would best be observed in group 1 (placebo). Upon observation of group 1 under original protocol, changes in CEP cells were not significant but there were changes in markers of inflammation, lipids, and HDL protein composition. A modification to the protocol and title were made to reflect this for groups 2 and 3: Hormonal regulation of HDL-C in Men.

Conditions

Healthy

Keywords

HDL; Insulin sensitivity; testosterone; estradiol; cholesterol

Outcome Measures

Primary Outcomes (1)

• Endothelial Progenitor Cells

  Number of CD33 + CD134+ cells as a percentage of all lymphocytes

  Baseline, Day 28

Secondary Outcomes (9)

• Follicle Stimulating Hormone (FSH)

  Baseline, 28 days

• Luteinizing Hormone Concentration (LH)

  Baseline, Day 28

• Testosterone Concentration

  Baseline, Day 28

• Estradiol Concentration

  Baseline, Day 28

• Sex Hormone Binding Globulin (SHBG)

  Baseline, Day 28

Study Arms (3)

Group 1

EXPERIMENTAL

Acyline 300 µg/kg injections every two weeks (2 doses) + placebo (no active ingredients) gel daily for 28 days + oral placebo pill daily for 28 days

Drug: Acyline

Group 2

EXPERIMENTAL

Acyline 300 µg/kg injections every two weeks (2 doses) + Testosterone gel 100 mg daily for 28 days + oral placebo pill daily for 28 days

Drug: Acyline + Testosterone gel

Group 3

EXPERIMENTAL

Acyline 300 μg/kg injections every two weeks (2 doses) for 28 days + Testosterone gel 100 mg daily for 28 days + oral anastrozole pill 1 mg daily for 28 days

Drug: Acyline + testosterone gel + anastrozole

Interventions

Acyline DRUG

Acyline 300 μg/kg injections every two weeks (2 doses) for 28 days + placebo Testosterone gel daily for 28 days + placebo oral anastrozole pill daily for 28 days

Also known as: placebo testosterone gel, placebo pill

Group 1

Acyline + Testosterone gel DRUG

Acyline 300 μg/kg injections every two weeks (2 doses) for 28 days + Testosterone gel 100 mg daily for 28 days + placebo oral pill 1 mg daily for 28 days

Also known as: Acyline, testosterone gel

Group 2

Acyline + testosterone gel + anastrozole DRUG

Acyline 300 μg/kg injections every two weeks (2 doses) for 28 days + Testosterone gel 100 mg daily for 28 days + oral anastrozole pill 1 mg daily for 28 days

Also known as: Acyline, Testosterone gel, Anastrozole

Group 3

Eligibility Criteria

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

You may qualify if:

• Males age 18-55 years
• Normal serum total testosterone (300 ng/dl-1000 ng/dl)
• Normal LH and FSH levels
• Taking no regular medications
• Normal baseline serum hematology, chemistry and liver function tests
• Agrees not to donate blood during the study
• Agrees to use a form of contraception during the study
• Subject must be able to comply with all study procedures

You may not qualify if:

• Clinically significant screening assessments or other relevant disease, allergy or surgery, as revealed by history, physical examination and/or laboratory assessments, which may limit participation or prevent completion of the study
• History of prostate cancer, breast cancer, or benign prostatic hypertrophy
• Prostate-specific antigen (PSA) \> 3.0
• History of regular, chronic testosterone or anabolic steroid use in the past year
• Chronic medical illness, prostate disease, or cardiovascular disease
• History of a bleeding disorder or need for anticoagulation
• Skin condition that might interfere with or be exacerbated by T gel use
• Sitting systolic blood pressure \> 180mm Hg or \<90 mm Hg or sitting diastolic blood pressure \>110 mm Hg or \< 60 mm Hg.
• History of clinically significant, untreated sleep apnea
• Participation in another drug-related research study within the past 2 months
• Participating in a regular physical relationship with a pregnant woman
• History of hypersensitivity to any of the study medications (T gel, anastrozole, acyline)
• History of medical or surgical therapy for benign prostatic hypertrophy
• Hematocrit \> 55%
• History of drug or alcohol abuse within last 6 months

Sponsors & Collaborators

• University of Washington: lead
• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): collaborator

Related Publications (28)

• Phillips GB. Is atherosclerotic cardiovascular disease an endocrinological disorder? The estrogen-androgen paradox. J Clin Endocrinol Metab. 2005 May;90(5):2708-11. doi: 10.1210/jc.2004-2011. Epub 2005 Feb 1.

  PMID: 15687329 BACKGROUND

• Bebb RA, Anawalt BD, Christensen RB, Paulsen CA, Bremner WJ, Matsumoto AM. Combined administration of levonorgestrel and testosterone induces more rapid and effective suppression of spermatogenesis than testosterone alone: a promising male contraceptive approach. J Clin Endocrinol Metab. 1996 Feb;81(2):757-62. doi: 10.1210/jcem.81.2.8636300.

  PMID: 8636300 BACKGROUND

• Wu FC, von Eckardstein A. Androgens and coronary artery disease. Endocr Rev. 2003 Apr;24(2):183-217. doi: 10.1210/er.2001-0025.

  PMID: 12700179 BACKGROUND

• Keating NL, O'Malley AJ, Smith MR. Diabetes and cardiovascular disease during androgen deprivation therapy for prostate cancer. J Clin Oncol. 2006 Sep 20;24(27):4448-56. doi: 10.1200/JCO.2006.06.2497.

  PMID: 16983113 BACKGROUND

• Smith MR. Changes in fat and lean body mass during androgen-deprivation therapy for prostate cancer. Urology. 2004 Apr;63(4):742-5. doi: 10.1016/j.urology.2003.10.063.

  PMID: 15072892 BACKGROUND

• Smith MR, Finkelstein JS, McGovern FJ, Zietman AL, Fallon MA, Schoenfeld DA, Kantoff PW. Changes in body composition during androgen deprivation therapy for prostate cancer. J Clin Endocrinol Metab. 2002 Feb;87(2):599-603. doi: 10.1210/jcem.87.2.8299.

  PMID: 11836291 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

• Braga-Basaria M, Dobs AS, Muller DC, Carducci MA, John M, Egan J, Basaria S. Metabolic syndrome in men with prostate cancer undergoing long-term androgen-deprivation therapy. J Clin Oncol. 2006 Aug 20;24(24):3979-83. doi: 10.1200/JCO.2006.05.9741.

  PMID: 16921050 BACKGROUND

• Werner N, Kosiol S, Schiegl T, Ahlers P, Walenta K, Link A, Bohm M, Nickenig G. Circulating endothelial progenitor cells and cardiovascular outcomes. N Engl J Med. 2005 Sep 8;353(10):999-1007. doi: 10.1056/NEJMoa043814.

  PMID: 16148285 BACKGROUND

• Werner N, Junk S, Laufs U, Link A, Walenta K, Bohm M, Nickenig G. Intravenous transfusion of endothelial progenitor cells reduces neointima formation after vascular injury. Circ Res. 2003 Jul 25;93(2):e17-24. doi: 10.1161/01.RES.0000083812.30141.74. Epub 2003 Jun 26.

  PMID: 12829619 BACKGROUND

• Vasa M, Fichtlscherer S, Aicher A, Adler K, Urbich C, Martin H, Zeiher AM, Dimmeler S. Number and migratory activity of circulating endothelial progenitor cells inversely correlate with risk factors for coronary artery disease. Circ Res. 2001 Jul 6;89(1):E1-7. doi: 10.1161/hh1301.093953.

  PMID: 11440984 BACKGROUND

• Dong C, Goldschmidt-Clermont PJ. Endothelial progenitor cells: a promising therapeutic alternative for cardiovascular disease. J Interv Cardiol. 2007 Apr;20(2):93-9. doi: 10.1111/j.1540-8183.2007.00251.x.

  PMID: 17391216 BACKGROUND

• Foresta C, Caretta N, Lana A, De Toni L, Biagioli A, Ferlin A, Garolla A. Reduced number of circulating endothelial progenitor cells in hypogonadal men. J Clin Endocrinol Metab. 2006 Nov;91(11):4599-602. doi: 10.1210/jc.2006-0763. Epub 2006 Aug 22.

  PMID: 16926245 BACKGROUND

• Foresta C, Zuccarello D, Biagioli A, De Toni L, Prana E, Nicoletti V, Ambrosini G, Ferlin A. Oestrogen stimulates endothelial progenitor cells via oestrogen receptor-alpha. Clin Endocrinol (Oxf). 2007 Oct;67(4):520-5. doi: 10.1111/j.1365-2265.2007.02918.x. Epub 2007 Jun 15.

  PMID: 17573901 BACKGROUND

• Foresta C, Zuccarello D, De Toni L, Garolla A, Caretta N, Ferlin A. Androgens stimulate endothelial progenitor cells through an androgen receptor-mediated pathway. Clin Endocrinol (Oxf). 2008 Feb;68(2):284-9. doi: 10.1111/j.1365-2265.2007.03036.x. Epub 2007 Sep 4.

  PMID: 17803706 BACKGROUND

• Iwakura A, Luedemann C, Shastry S, Hanley A, Kearney M, Aikawa R, Isner JM, Asahara T, Losordo DW. Estrogen-mediated, endothelial nitric oxide synthase-dependent mobilization of bone marrow-derived endothelial progenitor cells contributes to reendothelialization after arterial injury. Circulation. 2003 Dec 23;108(25):3115-21. doi: 10.1161/01.CIR.0000106906.56972.83. Epub 2003 Dec 15.

  PMID: 14676142 BACKGROUND

• Bergt C, Pennathur S, Fu X, Byun J, O'Brien K, McDonald TO, Singh P, Anantharamaiah GM, Chait A, Brunzell J, Geary RL, Oram JF, Heinecke JW. The myeloperoxidase product hypochlorous acid oxidizes HDL in the human artery wall and impairs ABCA1-dependent cholesterol transport. Proc Natl Acad Sci U S A. 2004 Aug 31;101(35):13032-7. doi: 10.1073/pnas.0405292101. Epub 2004 Aug 23.

  PMID: 15326314 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

• Mostaghel EA, Page ST, Lin DW, Fazli L, Coleman IM, True LD, Knudsen B, Hess DL, Nelson CC, Matsumoto AM, Bremner WJ, Gleave ME, Nelson PS. Intraprostatic androgens and androgen-regulated gene expression persist after testosterone suppression: therapeutic implications for castration-resistant prostate cancer. Cancer Res. 2007 May 15;67(10):5033-41. doi: 10.1158/0008-5472.CAN-06-3332.

  PMID: 17510436 BACKGROUND

• Page ST, Lin DW, Mostaghel EA, Hess DL, True LD, Amory JK, Nelson PS, Matsumoto AM, Bremner WJ. Persistent intraprostatic androgen concentrations after medical castration in healthy men. J Clin Endocrinol Metab. 2006 Oct;91(10):3850-6. doi: 10.1210/jc.2006-0968. Epub 2006 Aug 1.

  PMID: 16882745 BACKGROUND

• Page ST, Plymate SR, Bremner WJ, Matsumoto AM, Hess DL, Lin DW, Amory JK, Nelson PS, Wu JD. Effect of medical castration on CD4+ CD25+ T cells, CD8+ T cell IFN-gamma expression, and NK cells: a physiological role for testosterone and/or its metabolites. Am J Physiol Endocrinol Metab. 2006 May;290(5):E856-63. doi: 10.1152/ajpendo.00484.2005. Epub 2005 Dec 13.

  PMID: 16352669 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

• Mauras N, Lima J, Patel D, Rini A, di Salle E, Kwok A, Lippe B. Pharmacokinetics and dose finding of a potent aromatase inhibitor, aromasin (exemestane), in young males. J Clin Endocrinol Metab. 2003 Dec;88(12):5951-6. doi: 10.1210/jc.2003-031279.

  PMID: 14671195 BACKGROUND

• Lin EH, Hassan M, Li Y, Zhao H, Nooka A, Sorenson E, Xie K, Champlin R, Wu X, Li D. Elevated circulating endothelial progenitor marker CD133 messenger RNA levels predict colon cancer recurrence. Cancer. 2007 Aug 1;110(3):534-42. doi: 10.1002/cncr.22774.

  PMID: 17594720 BACKGROUND

• Hill JM, Zalos G, Halcox JP, Schenke WH, Waclawiw MA, Quyyumi AA, Finkel T. Circulating endothelial progenitor cells, vascular function, and cardiovascular risk. N Engl J Med. 2003 Feb 13;348(7):593-600. doi: 10.1056/NEJMoa022287.

  PMID: 12584367 BACKGROUND

• Gonzalo IT, Swerdloff RS, Nelson AL, Clevenger B, Garcia R, Berman N, Wang C. Levonorgestrel implants (Norplant II) for male contraception clinical trials: combination with transdermal and injectable testosterone. J Clin Endocrinol Metab. 2002 Aug;87(8):3562-72. doi: 10.1210/jcem.87.8.8710.

  PMID: 12161475 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 RESULT

• Rubinow KB, Tang C, Hoofnagle AN, Snyder CN, Amory JK, Heinecke JW, Page ST. Acute sex steroid withdrawal increases cholesterol efflux capacity and HDL-associated clusterin in men. Steroids. 2012 Apr;77(5):454-60. doi: 10.1016/j.steroids.2012.01.002. Epub 2012 Jan 15.

  PMID: 22266332 RESULT

MeSH Terms

Conditions

Insulin Resistance

Interventions

acyline; Anastrozole

Condition Hierarchy (Ancestors)

Hyperinsulinism; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Nitriles; Organic Chemicals; Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Stephanie T. Page, MD, PhD
• Organization: University of Washington

page@u.washington.edu

206-616-0483

Study Officials

• Stephanie Page, MD, PhD

  University of Washington

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor

Study Record Dates

• First Submitted: August 5, 2008
• First Posted: August 8, 2008
• Study Start: December 1, 2008
• Primary Completion: May 1, 2010
• Study Completion: May 1, 2010
• Last Updated: October 12, 2012
• Results First Posted: October 12, 2012

Record last verified: 2012-09