RA-2 13-cis Retinoic Acid (Isotretinoin)

Condition(s) targeted: Male Infertility; Klinefelter's Syndrome; Y-chromosome Microdeletions

Intervention: 13-cis retinoic acid (Drug)

Phase: Phase 2

Status: Recruiting

Sponsored by: University of Washington

Official(s) and/or principal investigator(s):
John K Amory, MD, MPH, Principal Investigator, Affiliation: University of Washington

Overall contact:
Iris Nielsen, Phone: 206-221-5473, Email: nielseni@uw.edu

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 intracytoplasmic sperm injection (IVF) and/or ICSI.

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

Study design: Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome: Total motile sperm

Secondary outcome:

13-cis retinoic acid serum level

Number of Participants with Serious and Non-Serious Adverse effects associated with treatment with 13-cis retinoic acid

13-cis retinoic acid Seminal Plasma Concentration

Detailed description: This is a 20 week, unblinded, single-arm pilot study to determine the impact of therapy with 13-cis retinoic acid 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. 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.

Minimum age: 21 Years. Maximum age: 60 Years. Gender(s): Male.

Criteria:

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 PHQ9 questionnaire.

- 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

Iris Nielsen, Phone: 206-221-5473, Email: nielseni@uw.edu

University of Washington Medical Center, Seattle, Washington 98195, United States; Recruiting
Iris Nielsen, Phone: 206-221-5473, Email: inielsen@uw.edu
John K Amory, MD, MPH, Principal Investigator

Related publications:

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

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.

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

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

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.

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.

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.

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.

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.

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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.

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.

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.

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

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

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

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.

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.

Starting date: August 2014
Last updated: August 4, 2015