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Men with infertility and normal hormone levels have few options for fertility treatment. Previous research work has suggested that men with infertility may have low levels of the active form of Vitamin A, called retinoic acid, in their testes. We think that giving men with low sperm counts retinoic acid may increase their sperm counts and improve their chances of fathering a pregnancy. We want to see if retinoic acid administration over twenty weeks can increase sperm production and help infertile men become fathers without the need for In vitro fertilization (IVF) and/or intracytoplasmic sperm injection (ICSI). We also want to see if adding calcitriol with retinoic acid will improve sperm motility in a sub-set of subjects.
This is a 20 week, unblinded, two-arm pilot study to determine the impact of therapy with 13-cis retinoic acid and calcitriol on sperm indices in infertile men. Twenty infertile men, ages 21-60 with abnormal sperm analyses will be enrolled for 20-week and given 20 mg 13-cis retinoic acid, twice daily. Subjects#11-#20 will also be administered calcitriol to see if adding calcitriol with Accutane will improve sperm motility. All subjects will be closely followed for side effects related to treatment. The impact of treatment on indices of spermatogenesis will be determined by monthly seminal fluid analyses.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 13-cis retinoic acid | Experimental | 20mg 13-cis retinoic acid twice daily (BID) with meals for 20 weeks |
|
| Calcitriol 0.25 mcg | Experimental | oral calcitriol 025 mcg BID subjects 11-20 for 20 weeks |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| 13-cis retinoic acid | Drug | Accutane is used for the treatment of severe acne |
|
| Measure | Description | Time Frame |
|---|---|---|
| Millions of Sperm Per Ejaculate | Millions of sperm per ejaculate in men treated with 13-cis retinoic acid | Up to 20-weeks |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| John K Amory, MD, MPH | University of Washington | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Washington Medical Center | Seattle | Washington | 98195 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 8102079 | Background | Jequier AM, Holmes SC. Primary testicular disease presenting as azoospermia or oligozoospermia in an infertility clinic. Br J Urol. 1993 Jun;71(6):731-5. doi: 10.1111/j.1464-410x.1993.tb16075.x. | |
| 9074589 | Background | de Kretser DM. Male infertility. Lancet. 1997 Mar 15;349(9054):787-90. doi: 10.1016/s0140-6736(96)08341-9. No abstract available. |
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| ID | Title | Description |
|---|---|---|
| FG000 | 13-cis Retinoic Acid + Oral Calcitriol | 20 mg 13-cis retinoic acid twice daily (BID) with meals for two weeks + oral calcitriol 0.25 mcg BID |
| FG001 | 13-cis Retinoic Acid | 20 mg 13-cis retinoic acid twice daily (BID) with meals for 20 weeks |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
Sixteen men completed all study procedures, and three men discontinued treatment early.
Not provided
| ID | Title | Description |
|---|---|---|
| BG000 | 13-cis Retinoic Acid | 20mg 13-cis retinoic acid twice daily (BID) with meals for 20 weeks 13-cis retinoic acid: Accutane is used for the treatment of severe acne |
| BG001 | 13-cis Retinoic Acid + Calcitriol 0.25 mcg |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Millions of Sperm Per Ejaculate | Millions of sperm per ejaculate in men treated with 13-cis retinoic acid | First 10 men received isotretinoin alone, next 10 men received both isotretinoin and calcitriol | Posted | Median | Inter-Quartile Range | Millions of sperm per ejaculate | Up to 20-weeks |
|
2 years
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 13-cis Retinoic Acid + Oral Calcitriol | 20 mg 13-cis retinoic acid twice daily (BID) with meals for two weeks + oral calcitriol 0.25 mcg BID |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Upper respiratory infection | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
Not provided
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. John Amory | University of Washington School of Medicine | 2066161727 | jamory@uw.edu |
Not provided
| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Oct 29, 2013 | Apr 26, 2021 | Prot_SAP_000.pdf |
| ICF | No | No | Yes | Informed Consent Form | Jan 22, 2014 | Apr 26, 2021 | ICF_001.pdf |
Not provided
| ID | Term |
|---|---|
| D007248 | Infertility, Male |
| D007713 | Klinefelter Syndrome |
| C536297 | Male sterility due to Y-chromosome deletions |
| D007246 | Infertility |
| ID | Term |
|---|---|
| D005832 | Genital Diseases, Male |
| D000091662 | Genital Diseases |
| D000091642 | Urogenital Diseases |
| D052801 | Male Urogenital Diseases |
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| ID | Term |
|---|---|
| D015474 | Isotretinoin |
| D002117 | Calcitriol |
| ID | Term |
|---|---|
| D012176 | Retinoids |
| D002338 | Carotenoids |
| D011090 | Polyenes |
| D000475 | Alkenes |
| D006839 |
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| Calcitriol | Drug | Calcitriol is a form of vitamin D given twice daily (BID) |
|
|
| 19247918 | Background | Schlegel PN. Nonobstructive azoospermia: a revolutionary surgical approach and results. Semin Reprod Med. 2009 Mar;27(2):165-70. doi: 10.1055/s-0029-1202305. Epub 2009 Feb 26. |
| 10506831 | Background | Napoli JL. Retinoic acid: its biosynthesis and metabolism. Prog Nucleic Acid Res Mol Biol. 1999;63:139-88. doi: 10.1016/s0079-6603(08)60722-9. |
| Background | Center for Disease Control. Infertility Facts,m accessed at http://www.ede.gov/nchs/fastats/fertile.htm (June 3, 2013) |
| 17905941 | Background | Doyle TJ, Braun KW, McLean DJ, Wright RW, Griswold MD, Kim KH. Potential functions of retinoic acid receptor A in Sertoli cells and germ cells during spermatogenesis. Ann N Y Acad Sci. 2007 Dec;1120:114-30. doi: 10.1196/annals.1411.008. Epub 2007 Sep 28. |
| 16461896 | Background | Koubova J, Menke DB, Zhou Q, Capel B, Griswold MD, Page DC. Retinoic acid regulates sex-specific timing of meiotic initiation in mice. Proc Natl Acad Sci U S A. 2006 Feb 21;103(8):2474-9. doi: 10.1073/pnas.0510813103. Epub 2006 Feb 6. |
| 18799751 | Background | Anderson EL, Baltus AE, Roepers-Gajadien HL, Hassold TJ, de Rooij DG, van Pelt AM, Page DC. Stra8 and its inducer, retinoic acid, regulate meiotic initiation in both spermatogenesis and oogenesis in mice. Proc Natl Acad Sci U S A. 2008 Sep 30;105(39):14976-80. doi: 10.1073/pnas.0807297105. Epub 2008 Sep 17. |
| 19465599 | Background | Chung SS, Wang X, Wolgemuth DJ. Expression of retinoic acid receptor alpha in the germline is essential for proper cellular association and spermiogenesis during spermatogenesis. Development. 2009 Jun;136(12):2091-100. doi: 10.1242/dev.020040. |
| 10529278 | Background | Dufour JM, Kim KH. Cellular and subcellular localization of six retinoid receptors in rat testis during postnatal development: identification of potential heterodimeric receptors. Biol Reprod. 1999 Nov;61(5):1300-8. doi: 10.1095/biolreprod61.5.1300. |
| 8388780 | Background | Lohnes D, Kastner P, Dierich A, Mark M, LeMeur M, Chambon P. Function of retinoic acid receptor gamma in the mouse. Cell. 1993 May 21;73(4):643-58. doi: 10.1016/0092-8674(93)90246-m. |
| 8394014 | Background | Lufkin T, Lohnes D, Mark M, Dierich A, Gorry P, Gaub MP, LeMeur M, Chambon P. High postnatal lethality and testis degeneration in retinoic acid receptor alpha mutant mice. Proc Natl Acad Sci U S A. 1993 Aug 1;90(15):7225-9. doi: 10.1073/pnas.90.15.7225. |
| 8557197 | Background | Kastner P, Mark M, Leid M, Gansmuller A, Chin W, Grondona JM, Decimo D, Krezel W, Dierich A, Chambon P. Abnormal spermatogenesis in RXR beta mutant mice. Genes Dev. 1996 Jan 1;10(1):80-92. doi: 10.1101/gad.10.1.80. |
| 16586441 | Background | Ghyselinck NB, Vernet N, Dennefeld C, Giese N, Nau H, Chambon P, Viville S, Mark M. Retinoids and spermatogenesis: lessons from mutant mice lacking the plasma retinol binding protein. Dev Dyn. 2006 Jun;235(6):1608-22. doi: 10.1002/dvdy.20795. |
| 1398387 | Background | Hoting VE, Schutte B, Schirren C. [Isotretinoin treatment of acne conglobata. Andrologic follow-up]. Fortschr Med. 1992 Aug 20;110(23):427-30. German. |
| 3159708 | Background | Vogt HJ, Ewers R. [13-cis-Retinoic acid and spermatogenesis. Spermatological and impulse cytophotometric studies]. Hautarzt. 1985 May;36(5):281-6. German. |
| 3481225 | Background | Torok L, Kadar L, Kasa M. Spermatological investigations in patients treated with etretinate and isotretinoin. Andrologia. 1987 Nov-Dec;19(6):629-33. doi: 10.1111/j.1439-0272.1987.tb01915.x. |
| 23413144 | Background | Nya-Ngatchou JJ, Arnold SL, Walsh TJ, Muller CH, Page ST, Isoherranen N, Amory JK. Intratesticular 13-cis retinoic acid is lower in men with abnormal semen analyses: a pilot study. Andrology. 2013 Mar;1(2):325-31. doi: 10.1111/j.2047-2927.2012.00033.x. Epub 2012 Nov 29. |
| Background | WHO Laboratory Manual for the Examination of Human Semen and Sperm-Cervical Mucus Interaction |
| 6795047 | Background | Christiansen C, Christensen MS, Rodbro P, Hagen C, Transbol I. Effect of 1,25-dihydroxy-vitamin D3 in itself or combined with hormone treatment in preventing postmenopausal osteoporosis. Eur J Clin Invest. 1981 Aug;11(4):305-9. doi: 10.1111/j.1365-2362.1981.tb02121.x. |
| 3926808 | Background | Riggs BL, Nelson KI. Effect of long term treatment with calcitriol on calcium absorption and mineral metabolism in postmenopausal osteoporosis. J Clin Endocrinol Metab. 1985 Sep;61(3):457-61. doi: 10.1210/jcem-61-3-457. |
| 3035879 | Background | Falch JA, Odegaard OR, Finnanger AM, Matheson I. Postmenopausal osteoporosis: no effect of three years treatment with 1,25-dihydroxycholecalciferol. Acta Med Scand. 1987;221(2):199-204. doi: 10.1111/j.0954-6820.1987.tb01267.x. |
| 2325571 | Background | Caniggia A, Nuti R, Lore F, Martini G, Turchetti V, Righi G. Long-term treatment with calcitriol in postmenopausal osteoporosis. Metabolism. 1990 Apr;39(4 Suppl 1):43-9. doi: 10.1016/0026-0495(90)90272-e. |
| 2913914 | Background | Ott SM, Chesnut CH 3rd. Calcitriol treatment is not effective in postmenopausal osteoporosis. Ann Intern Med. 1989 Feb 15;110(4):267-74. doi: 10.7326/0003-4819-110-4-267. |
| 11502787 | Background | Gallagher JC, Fowler SE, Detter JR, Sherman SS. Combination treatment with estrogen and calcitriol in the prevention of age-related bone loss. J Clin Endocrinol Metab. 2001 Aug;86(8):3618-28. doi: 10.1210/jcem.86.8.7703. |
oral calcitriol 025 mcg BID subjects 11-20 for 20 weeks
Calcitriol: Calcitriol is a form of vitamin D given twice daily (BID)
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race/Ethnicity, Customized | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
|
|
| 0 |
| 10 |
| 0 |
| 10 |
| 1 |
| 10 |
| EG001 | 13-cis Retinoic Acid | 20 mg 13-cis retinoic acid twice daily (BID) with meals for 20 weeks | 0 | 10 | 0 | 10 | 1 | 10 |
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| D058533 | Sex Chromosome Disorders of Sex Development |
| D012734 | Disorders of Sex Development |
| D014564 | Urogenital Abnormalities |
| D052776 | Female Urogenital Diseases |
| D005261 | Female Urogenital Diseases and Pregnancy Complications |
| D025064 | Sex Chromosome Disorders |
| D025063 | Chromosome Disorders |
| D000013 | Congenital Abnormalities |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D030342 | Genetic Diseases, Inborn |
| D006058 | Gonadal Disorders |
| D004700 | Endocrine System Diseases |
| D007006 | Hypogonadism |
| Hydrocarbons, Acyclic |
| D006838 | Hydrocarbons |
| D009930 | Organic Chemicals |
| D053138 | Cyclohexenes |
| D003510 | Cyclohexanes |
| D003516 | Cycloparaffins |
| D006840 | Hydrocarbons, Alicyclic |
| D006844 | Hydrocarbons, Cyclic |
| D013729 | Terpenes |
| D010860 | Pigments, Biological |
| D001685 | Biological Factors |
| D004100 | Dihydroxycholecalciferols |
| D006887 | Hydroxycholecalciferols |
| D002762 | Cholecalciferol |
| D002782 | Cholestenes |
| D002776 | Cholestanes |
| D013256 | Steroids |
| D000072473 | Fused-Ring Compounds |
| D011083 | Polycyclic Compounds |
| D013261 | Sterols |
| D014807 | Vitamin D |
| D012632 | Secosteroids |
| D008563 | Membrane Lipids |
| D008055 | Lipids |