The overarching goal of this application for a K24 Midcareer Investigator in Patient-Oriented Research is to foster training of promising junior investigators in high quality patient-oriented research in male reproduction. The proposed principal investigator, Dr. Amory, has established himself as a gifted researcher and is a dedicated mentor to junior faculty and trainees. With this award, Dr. Amory hopes to continue as a leader in patient-oriented research in the area of male reproduction and to enhance the educational training of clinical trainees through hands-on mentorship, facilitating their individua growth as well as the future of translational research in male reproduction. Infertility affects 10 15% of all couples, and infertility attributable to the male partner accounts for 30-40% of all cases of infertility. The most common form of male infertility involves some type of impairment in spermatogenesis. Unfortunately, most men with infertility do not have a medically treatable cause. Surgical sperm extraction coupled with either in vitro fertilization or intra-cytoplasmic sperm injection offers hope of fertility; however, these procedures are invasive, expensive, unsuccessful in many cases, and don't address the underlying cause of infertility. Therefore, new approaches to the treatment of male infertility are needed. The objective of the work proposed in this application is to obtain knowledge useful to understand the role of retinoic acid in spermatogenesis and male infertility. It is well established in animal models that testicular biosynthesis of retinoic acid is required for spermatogonial differentiation, spermiogenesis and spermiation. However, in contrast to the situation in experimental animals, there has been almost no work examining the role of retinoic acid in human spermatogenesis. Recently, our group found that intratesticular retinoic acid is significantly reduced in men who have sub-normal sperm parameters, suggesting that intratesticular retinoic acid deficiency may be related to impaired spermatogenesis in man. With this grant, we propose to examine the role of intratesticular retinoic acid in men presenting with male infertility. In the first aim of this proosal, we will investigate the relationship between intratesticular retinoic acid and spermatogenesis using an observational study in testicular tissue from men undergoing sperm retrieval procedures for infertility treatment. In the second aim, we will conduct a pilot clinical trial of retinoic acid administration to men with infertility from poor sperm quality to determine whether retinoic acid improves ejaculated sperm parameters. Taken together, these experiments will greatly improve our understanding of the relationship between intratesticular retinoic acid and spermatogenesis in man, and have the potential to initiate a novel medical approach to the treatment of male infertility.

Public Health Relevance

This application supports ongoing training in patient-oriented research for the next generation of clinicians studying male reproduction. The proposed research focuses on new treatments for male infertility and the development of new methods of male contraception. Specifically, we seek to determine if intratesticular retinoic acid deficiency plays a role in male infertility, and if inhibition of testicular retinoic acid biosynthesis can fuction as a safe, effective and reversible form of male contraception.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Midcareer Investigator Award in Patient-Oriented Research (K24)
Project #
1K24HD082231-01
Application #
8803521
Study Section
Pediatrics Subcommittee (CHHD)
Program Officer
Moss, Stuart B
Project Start
2015-05-01
Project End
2020-01-31
Budget Start
2015-05-01
Budget End
2016-01-31
Support Year
1
Fiscal Year
2015
Total Cost
$127,508
Indirect Cost
$9,445
Name
University of Washington
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Rubinow, Katya B; Chao, Jing H; Hagman, Derek et al. (2017) Circulating sex steroids coregulate adipose tissue immune cell populations in healthy men. Am J Physiol Endocrinol Metab 313:E528-E539
Amory, J K; Ostrowski, K A; Gannon, J R et al. (2017) Isotretinoin administration improves sperm production in men with infertility from oligoasthenozoospermia: a pilot study. Andrology 5:1115-1123
Amory, John K; Louden, Diana K N; McKinney, Christy et al. (2017) Scholarly productivity and professional advancement of junior researchers receiving KL2, K23, or K08 awards at a large public research institution. J Clin Transl Sci 1:140-143
Thirumalai, Arthi; Berkseth, Kathryn E; Amory, John K (2017) Treatment of Hypogonadism: Current and Future Therapies. F1000Res 6:68
Jing, Jing; Nelson, Cara; Paik, Jisun et al. (2017) Physiologically Based Pharmacokinetic Model of All-trans-Retinoic Acid with Application to Cancer Populations and Drug Interactions. J Pharmacol Exp Ther 361:246-258
Roth, Mara Y; Amory, John K (2016) Beyond the Condom: Frontiers in Male Contraception. Semin Reprod Med 34:183-90
Berkseth, Kathryn E; Thirumalai, Arthi; Amory, John K (2016) Pharmacologic Therapy in Men's Health: Hypogonadism, Erectile Dysfunction, and Benign Prostatic Hyperplasia. Med Clin North Am 100:791-805
Amory, John K (2016) Male contraception. Fertil Steril 106:1303-1309
Cooper, Lori A; Page, Stephanie T; Amory, John K et al. (2015) The association of obesity with sex hormone-binding globulin is stronger than the association with ageing--implications for the interpretation of total testosterone measurements. Clin Endocrinol (Oxf) 83:828-33
Arnold, Samuel L; Kent, Travis; Hogarth, Cathryn A et al. (2015) Importance of ALDH1A enzymes in determining human testicular retinoic acid concentrations. J Lipid Res 56:342-57

Showing the most recent 10 out of 11 publications