Inhibins are gonadal glycoproteins produced by the granulosa cells and sertoli cells under the influence of FSH. The fully processed form of the inhibin molecule has a molecular weight of approximately 32 kDa and consists of the two distinct chains (α and β), linked by disulfide bridges. Inhibin-α subunit pairs with βA and βB subunits to form Inhibin A and Inhibin B respectively. Inhibins control androgen secretion and germ cell proliferation. High follicular levels of inhibin A are associated with continued follicular growth and ovulation(1). Equine fetal testes and fetal ovaries secrete significantly larger amounts of inhibin B than adult testes and ovaries. Plasma concentrations of Inhibin A are significantly higher during the growth of preovulatory follicles than during the transitional anovulatory follicles. Recent findings suggested a decrease in intrafollicular-free insulin-like growth factor I, inhibin A, vascular endothelial growth factor, and prolactin during the final stages of follicular growth. This is the first documented occurrence of dynamic changes among intrafollicular factors and hormones during the stages of follicle dominance and as ovulation approaches(2). Granulosa cell tumors (GCTs) are the most common form of ovarian neoplasm in mares, accounting for more than 85% of all tumors of the reproductive tract in female horses(3). Elevated levels of Inhibin B are implicated in granulosa cell tumors of ovary(4). Measurement of concentrations of inhibin B and testosterone in serum are useful to support a presumptive diagnosis of GCTs in mares(5).
In canines, inhibin B can be used as marker for tumors(6). Adrenocortical tumors and pituitary-dependent hyperadrenocorticism but not pheochromocytoma are associated with increased serum inhibin concentration; undetectable inhibin is highly supportive of pheochromocytoma in neutered dogs with adrenal tumors(7).
In studies of bovine reproduction, results from a study by Kaneko et al, clearly indicate that the bull testis produces inhibin A and B and secretes these hormones in high concentrations into the circulation during postnatal development(8). Inhibin B has also been reported as a biomarker of spermatogenesis in toxicological studies(9).
The expression of inhibin isotypes increases progressively in the testis of mice with increasing postnatal age, suggesting that inhibin is associated with a negative feedback signal for FSH in testicular maturation(10). Testicular toxicity is an important safety endpoint in drug development and risk assessment, but reliable and translatable biomarkers for predicting injury have eluded researchers. Recently, the Health and Environment Sciences Institute€™s Developmental Reproductive Toxicity Technical Committee (HESI DART) hosted a consortium of companies to evaluate inhibin B as a potential biomarker for testicular toxicity and summarized the results. Beyond technical performance, the consortium was most interested in the correlation between decreases in circulating inhibin B levels and the development of testicular pathology in the rat(11).
References:
1. McKinnon et al. Equine Reproduction Second Edition, 2011
2. Takeo et al. Immunotherapy using inhibin antiserum enhanced the efficacy of equine chorionic gonadotropin on superovulation in major inbred and outbred mice strains Theriogenology. 2016:15;86(5):1341-6
3. McCue PM, Roser JF, Munro CJ, et al. Granulosa cell tumors of the equine ovary. Vet Clin North Am Equine Pract 2006; 22:799-817.
4. McCue PM. Equine granulosa cell tumors, in Proceedings. Am Assoc Equine Pract 1992; 38:587-593.
5. Gee et al. Granulosa theca cell tumour in a pregnant mare: concentrations of inhibin and testosterone in serum before and after surgery. N Z Vet J. 2012 Mar;60(2):160-3.
6. Brömel et al. Serum inhibin concentration in dogs with adrenal gland disease and in healthy dogs J Vet Intern Med. 2013 Jan-Feb;27(1):76-82.
7. Yu et al, Comparative immunohistochemical characterization of canine seminomas and Sertoli cell tumors. J Vet Sci. 2009 ;10(1):1-7.
8. Kaneko et al, Changes in circulating and testicular levels of inhibin A and B during postnatal development in bulls J Reprod Dev.2006 Dec;52(6):741-9
9. Ali Said Faqi. A Comprehensive Guide to Toxicology in Nonclinical Drug Development Second Edition, 2013
10. Kim et al, The expression and localization of inhibin isotypes in mouse testis during postnatal development. J Vet Sci. 2008; 9(4):345-9.
11. Edward et al, SOT Symposium Highlight: Translatable Indicators of Testicular Toxicity: Inhibin B, MicroRNAs, and Sperm Signatures Toxicol Sci. 2013 ; 136(2): 265€“273.
12. HHS Publication, 5th ed., 2007. Biosafety in Microbiological and Biomedical Laboratories. Available http://www.cdc.gov/biosafety/publications/bmbl5/BMBL5
13. DHHS (NIOSH) Publication No. 78€“127, August 1976. Current Intelligence Bulletin 13 - Explosive Azide Hazard. Available http:// www.cdc.gov/niosh.
14. Approved Guideline €“ Procedures for the Handling and Processing of Blood Specimens, H18-A3. 2004. Clinical and Laboratory Standards Institute.
15. Kricka L. Interferences in immunoassays €“ still a threat. Clin Chem 2000; 46: 1037€“1038.
