HOP-3 Manipulation of the Intratesticular Hormonal Milieu With Exogenous Testosterone - Study Results

Study Type:	Interventional
Study Design:	Allocation: Randomized; Endpoint Classification: Safety/Efficacy Study; Intervention Model: Parallel Assignment; Masking: Open Label; Primary Purpose: Treatment
Condition:	Healthy Males
Interventions:	Drug: Acyline Other: placebo hCG (no active ingredient) Drug: hCG (human chorionic gonadotropin) Drug: Testosterone gel

Participant Flow

Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
Subjects were recruited using rosters from prior research studies and newspaper and online advertisements.

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
2 of 61 men decided not to enroll. 19 failed inclusion criteria, 1 withdrew consent before study procedures, 1 dropped out after Day 1, and 1 was withdrawn by the investigator for syncopal reaction. 6 did not suppress serum luteinizing hormone(affecting intratesticular testosterone)and were excluded from analysis. 31 completed the study.

Reporting Groups

	Description
Acyline Plus Placebo	Acyline (ACY) 300 ug/kg subcutaneous (SQ) injections on Day 1 plus SQ placebo hCG every other day(q.o.d) (5 doses) for 10 days
Acyline Plus 15 IU hCG	ACY 300 ug/kg SQ on Day 1 plus SQ 15 IU hCG q.o.d (5 doses) for 10 days
Acyline Plus 60 IU hCG	ACY 300 ug/kg SQ Day 1 + 60 IU hCG SQ q.o.d (5 doses) for 10 days
Acyline Plus 125 IU hCG	ACY 300 ug/kg SQ Day 1 + 125 IU hCG SQ q.o.d (5 doses) for 10 days
Acyline Plus Testosterone Gel	ACY 300 ug/kg SQ on Day 1 + Testosterone gel 75 mg/day daily for 10 days

Participant Flow: Overall Study

	Acyline Plus Placebo	Acyline Plus 15 IU hCG	Acyline Plus 60 IU hCG	Acyline Plus 125 IU hCG	Acyline Plus Testosterone Gel
STARTED	8	8	8	8	8
COMPLETED	6 ^[1]	7 ^[2]	5 ^[3]	5 ^[4]	8
NOT COMPLETED	2	1	3	3	0

[1]	1 withdrew consent prior to procedures; 1 excluded from analysis (low serum LH)
[2]	1 excluded from analysis (low serum LH)
[3]	1 dropped out after Day 1 visit, 2 excluded from analysis (low serum LH)
[4]	1 withdrawn by investigator for syncopal reaction , 2 excluded from analysis (low serum LH)

Baseline Characteristics

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Reporting Groups

	Description
Acyline Plus Placebo	Acyline (ACY) 300 ug/kg subcutaneous (SQ) injections on Day 1 plus SQ placebo hCG every other day(q.o.d) (5 doses) for 10 days
Acyline Plus 15 IU hCG	ACY 300 ug/kg SQ on Day 1 plus SQ 15 IU hCG q.o.d (5 doses) for 10 days
Acyline Plus 60 IU hCG	ACY 300 ug/kg SQ Day 1 + 60 IU hCG SQ q.o.d (5 doses) for 10 days
Acyline Plus 125 IU hCG	ACY 300 ug/kg SQ Day 1 + 125 IU hCG SQ q.o.d (5 doses) for 10 days
Acyline Plus Testosterone Gel	ACY 300 ug/kg SQ on Day 1 + Testosterone gel 75 mg/day daily for 10 days

Baseline Measures

	Acyline Plus Placebo	Acyline Plus 15 IU hCG	Acyline Plus 60 IU hCG	Acyline Plus 125 IU hCG	Acyline Plus Testosterone Gel	Total
Number of Participants [units: participants]	6	7	5	5	8	31
Age, Customized [units: years] Median ( Inter-Quartile Range )	21 ( 20 to 26 )	25 ( 20 to 29 )	22 ( 20 to 24 )	22 ( 21 to 26 )	22 ( 20 to 24 )	22 ( 20 to 26 )
Gender [units: participants]
Female	0	0	0	0	0	0
Male	6	7	5	5	8	31
Body Mass Index (BMI) [units: kg/m^2] Median ( Inter-Quartile Range )	24.8 ( 23.6 to 26.3 )	24.1 ( 23.2 to 26.7 )	24.9 ( 21.2 to 26.3 )	25.8 ( 22.9 to 26 )	23.7 ( 21.1 to 25.4 )	24.1 ( 22.9 to 26.3 )
Serum Luteinizing Hormone (LH) [units: IU/L] Median ( Inter-Quartile Range )	3.5 ( 3.1 to 4.8 )	3.0 ( 2.6 to 4.9 )	3.4 ( 3.4 to 4.9 )	2.9 ( 2.3 to 3.7 )	3.8 ( 2.6 to 4.6 )	3.4 ( 2.6 to 4.9 )
Serum Follicle Simulating Hormone (FSH) [units: IU/L] Median ( Inter-Quartile Range )	2.7 ( 1.2 to 3.4 )	2.4 ( 2 to 2.8 )	2.6 ( 2.2 to 3.2 )	2.2 ( 1.9 to 2.5 )	1.9 ( 1.3 to 2.8 )	2.4 ( 1.5 to 3.0 )
Serum Testosterone (T) [units: nmol/L] Median ( Inter-Quartile Range )	13.0 ( 11.3 to 16.9 )	15.0 ( 11.4 to 20.9 )	14.2 ( 12.7 to 14.9 )	16.8 ( 14.4 to 18.6 )	15.0 ( 13.7 to 18.3 )	14.6 ( 12 to 17.3 )
Serum Dihydrotestosterone (DHT) [units: nmol/L] Median ( Inter-Quartile Range )	1.0 ( 0.7 to 1.5 )	1.3 ( 0.9 to 1.7 )	1.2 ( 1 to 1.3 )	0.9 ( 0.7 to 1.5 )	1.1 ( 1.1 to 1.2 )	1.1 ( 0.9 to 1.4 )
Serum Estradiol [units: pmol/L] Median ( Inter-Quartile Range )	89 ( 47 to 150 )	65 ( 34 to 125 )	62 ( 48 to 78 )	77 ( 44 to 95 )	86 ( 54 to 95 )	77 ( 46 to 104 )
Serum 17-Hydroxyprogesterone [units: nmol/L] Median ( Inter-Quartile Range )	4.7 ( 3.8 to 7.8 )	4.9 ( 4.2 to 6.5 )	5.9 ( 5.1 to 7.6 )	4.3 ( 4 to 4.5 )	4.6 ( 3.7 to 5.4 )	4.9 ( 3.9 to 6.5 )
Intratesticular Testosterone (ITT-T) [units: nmol/L] Median ( Inter-Quartile Range )	3467 ( 2508 to 3839 )	2425 ( 1700 to 3380 )	1821 ( 1753 to 2412 )	3502 ( 2305 to 3959 )	2933 ( 1527 to 3390 )	2508 ( 1753 to 3502 )
Intratesticular Dihydrotestosterone (ITT-DHT) [units: nmol/L] Median ( Inter-Quartile Range )	18.0 ( 11.9 to 24.5 )	5.0 ( 4.5 to 11 )	7.6 ( 7.1 to 21.3 )	18.8 ( 11.1 to 22.2 )	12.9 ( 7.9 to 15.5 )	11.9 ( 7.3 to 21.3 )

Outcome Measures

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1. Primary:

Serum Testosterone (T) [ Time Frame: 10 days ]

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2. Primary:

Serum Luteinizing Hormone (LH) [ Time Frame: 10 days ]

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3. Primary:

Serum Follicle Stimulating Hormone (FSH) [ Time Frame: 10 days ]

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4. Primary:

Intratesticular Testosterone (ITT-T) [ Time Frame: 10 days ]

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Serious Adverse Events

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Other Adverse Events

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More Information

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Certain Agreements:

All Principal Investigators ARE employed by the organization sponsoring the study.

Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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Results Point of Contact:

Name/Title: Mara Roth, MD
Organization: University of Washington
phone: 206-221-0519
e-mail: mylang@u.washington.edu

Publications of Results:

Roth MY, Page ST, Lin K, Anawalt BD, Matsumoto AM, Snyder CN, Marck BT, Bremner WJ, Amory JK. Dose-dependent increase in intratesticular testosterone by very low-dose human chorionic gonadotropin in normal men with experimental gonadotropin deficiency. J Clin Endocrinol Metab. 2010 Aug;95(8):3806-13. Epub 2010 May 19.

Other Publications:

[No authors listed] Contraceptive efficacy of testosterone-induced azoospermia in normal men. World Health Organization Task Force on methods for the regulation of male fertility. Lancet. 1990 Oct 20;336(8721):955-9.

Wu FC, Farley TM, Peregoudov A, Waites GM. Effects of testosterone enanthate in normal men: experience from a multicenter contraceptive efficacy study. World Health Organization Task Force on Methods for the Regulation of Male Fertility. Fertil Steril. 1996 Mar;65(3):626-36.

Anawalt BD, Bebb RA, Bremner WJ, Matsumoto AM. A lower dosage levonorgestrel and testosterone combination effectively suppresses spermatogenesis and circulating gonadotropin levels with fewer metabolic effects than higher dosage combinations. J Androl. 1999 May-Jun;20(3):407-14.

Zirkin BR, Santulli R, Awoniyi CA, Ewing LL. Maintenance of advanced spermatogenic cells in the adult rat testis: quantitative relationship to testosterone concentration within the testis. Endocrinology. 1989 Jun;124(6):3043-9.

Coviello AD, Matsumoto AM, Bremner WJ, Herbst KL, Amory JK, Anawalt BD, Sutton PR, Wright WW, Brown TR, Yan X, Zirkin BR, Jarow JP. Low-dose human chorionic gonadotropin maintains intratesticular testosterone in normal men with testosterone-induced gonadotropin suppression. J Clin Endocrinol Metab. 2005 May;90(5):2595-602. Epub 2005 Feb 15.

Coviello AD, Bremner WJ, Matsumoto AM, Herbst KL, Amory JK, Anawalt BD, Yan X, Brown TR, Wright WW, Zirkin BR, Jarow JP. Intratesticular testosterone concentrations comparable with serum levels are not sufficient to maintain normal sperm production in men receiving a hormonal contraceptive regimen. J Androl. 2004 Nov-Dec;25(6):931-8.

Awoniyi CA, Sprando RL, Santulli R, Chandrashekar V, Ewing LL, Zirkin BR. Restoration of spermatogenesis by exogenously administered testosterone in rats made azoospermic by hypophysectomy or withdrawal of luteinizing hormone alone. Endocrinology. 1990 Jul;127(1):177-84.

Chen H, Chandrashekar V, Zirkin BR. Can spermatogenesis be maintained quantitatively in intact adult rats with exogenously administered dihydrotestosterone? J Androl. 1994 Mar-Apr;15(2):132-8.

Meriggiola MC, Costantino A, Bremner WJ, Morselli-Labate AM. Higher testosterone dose impairs sperm suppression induced by a combined androgen-progestin regimen. J Androl. 2002 Sep-Oct;23(5):684-90.

Responsible Party:	William J Bremner, MD, PhD, University of Washington
ClinicalTrials.gov Identifier:	NCT00839319 History of Changes
Other Study ID Numbers:	27158-D, U54HD012629
Study First Received:	February 6, 2009
Results First Received:	October 15, 2010
Last Updated:	February 1, 2011
Health Authority:	United States: Food and Drug Administration; United States: Institutional Review Board