RA-2 13-cis Retinoic Acid (Isotretinoin)

Male Infertility Clinical Trial

— RA-2  

Official title:

A Pilot Trial of 13-cis Retinoic Acid (Isotretinoin) for the Treatment of Men With Oligoasthenoteratozoospermia

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02061384
• Other study ID #: STUDY00000564
• Status: Completed
• Phase: Phase 2
• Start date: August 2014
• Est. completion date: December 2018

Study information

• Verified date: June 2021
• Source: University of Washington
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 20
• Est. completion date: December 2018
• Est. primary completion date: December 2018
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 21 Years to 60 Years

Eligibility

Inclusion Criteria:

• Subjects will be infertile men (no pregnancy with partner with normal cycles and normal hysterosalpingogram despite >1 year of unprotected intercourse).

• Abnormal sperm analyses with a total, motile sperm count of less than 10 million sperm as assessed by semen analysis on two occasions separated by one week.

• In the opinion of the investigator, is able to comply with the protocol, understand and sign an informed consent and HIPAA (Health Insurance Portability and Accountability Act ) form.

Exclusion Criteria:

• Men participating in another clinical trial

• Men not living in the catchment area of the clinic

• Clinically significant abnormal findings at screening

• Known genetic infertility (e.g. Klinefelter syndrome or Y-chromosome microdeletions),

• Hypogonadotropic hypogonadism (that might respond to gonadotropin injections),

• The use of anabolic steroids, illicit drugs, or the consumption of more than 4 alcoholic beverages daily

• Severe mental health problems requiring medications

• Current therapy with retinoic acid (e.g. Accutane) or vitamin A.

• Score of greater than 15 on the Patient health questionnaire (PHQ9).

• Abnormal serum chemistry values according to local laboratory normal values which indicate liver or kidney dysfunction. Other abnormal lab values may also be exclusionary, at the discretion of the investigator

• Men with a personal history of serious psychiatric disorders

• Men currently receiving tetracycline containing medications

• Men currently receiving phenytoin

• Men with a history of inflammatory bowel disease

• Men with a history of bone disease

• Men who have used isotretinoin within eight weeks of the start of dosing

• Men with elevated serum triglycerides

Related Conditions & MeSH terms

• Infertility
• Infertility, Male
• Klinefelter Syndrome
• Klinefelter's Syndrome
• Male Infertility
• Y-chromosome Microdeletions

Intervention

Drug:
• 13-cis retinoic acid
Accutane is used for the treatment of severe acne
• Calcitriol
Calcitriol is a form of vitamin D given twice daily (BID)

Locations

Country	Name	City	State
United States	University of Washington Medical Center	Seattle	Washington

Sponsors (1)

Lead Sponsor	Collaborator
University of Washington

Country where clinical trial is conducted

United States, 

References & Publications (25)

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. — View Citation

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Center for Disease Control. Infertility Facts,m accessed at http://www.ede.gov/nchs/fastats/fertile.htm (June 3, 2013)

Christiansen C, Christensen MS, Rødbro P, Hagen C, Transbøl 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. — View Citation

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. — View Citation

de Kretser DM. Male infertility. Lancet. 1997 Mar 15;349(9054):787-90. Review. — View Citation

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. Epub 2007 Sep 28. — View Citation

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. — View Citation

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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. — View Citation

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. — View Citation

Hoting VE, Schütte B, Schirren C. [Isotretinoin treatment of acne conglobata. Andrologic follow-up]. Fortschr Med. 1992 Aug 20;110(23):427-30. German. — View Citation

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. — View Citation

Kastner P, Mark M, Leid M, Gansmuller A, Chin W, Grondona JM, Décimo D, Krezel W, Dierich A, Chambon P. Abnormal spermatogenesis in RXR beta mutant mice. Genes Dev. 1996 Jan 1;10(1):80-92. — View Citation

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. Epub 2006 Feb 6. — View Citation

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. — View Citation

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. — View Citation

Napoli JL. Retinoic acid: its biosynthesis and metabolism. Prog Nucleic Acid Res Mol Biol. 1999;63:139-88. Review. — View Citation

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. — View Citation

Ott SM, Chesnut CH 3rd. Calcitriol treatment is not effective in postmenopausal osteoporosis. Ann Intern Med. 1989 Feb 15;110(4):267-74. — View Citation

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. — View Citation

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. Review. — View Citation

Török L, Kádár L, Kása M. Spermatological investigations in patients treated with etretinate and isotretinoin. Andrologia. 1987 Nov-Dec;19(6):629-33. — View Citation

Vogt HJ, Ewers R. [13-cis-Retinoic acid and spermatogenesis. Spermatological and impulse cytophotometric studies]. Hautarzt. 1985 May;36(5):281-6. German. — View Citation

World Health Organization. [Laboratory manual of the WHO for the examination of human semen and sperm-cervical mucus interaction]. Ann Ist Super Sanita. 2001;37(1):I-XII, 1-123. Italian. — View Citation

* Note: There are 25 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Millions of Sperm Per Ejaculate	Millions of sperm per ejaculate in men treated with 13-cis retinoic acid	Up to 20-weeks