Abstract
The purpose of this study was to assess whether male rats whose testosterone levels were suppressed to castration levels (<0.5 ng/mL) for a 1-year period by the sustained delivery of orntide acetate, a GnRH antagonist, would return to fertility (ie, produce offspring) after serum testosterone returned to control levels. Male rats comprising a treatment group (orntide microspheres, dose=27 mg/kg/y), a vehicle control group, and a control group of proven male breeders were used. For the treatment and vehicle control groups, serum orntide and testosterone levels were monitored at periodic intervals for 14 months from the initiation of treatment. After serum testosterone levels returned to vehicle control levels and orntide serum levels were no longer discernible for the treated group, each of the animals was housed with 2 drug-naive, female, proven breeders. All the breeder females produced offspring with the exception of 1 female housed with a male rat from the treatment group and the 2 females housed with a single male rat from the vehicle control group. The mean size and weight of the litters from each group were not statistically different. Further, fertility of the offspring from each group was assessed. The male and female offspring studied were all shown to be fertile. The results suggest that lack of fertility due to testosterone suppression in male rats is reversible after cessation of treatment with the GnRH analog, orntide.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Okada H. One-and three-month release injectable microspheres of the LH-RH superagonist leuprorelin acetate. Adv Drug Deliv Rev. 1997; 28: 43–70.
Pucarelli I, Segni M, Ortore M, Arcadi E, Pasquino AM. Effects of combined gonadotropin-releasing hormone agonist and growth hormone therapy on adult height in precocious puberty: a further contribution. J Pediatr Endocrinol Metab. 2003; 16: 1005–1010.
Fontana D, Mari M, Martinelli A, et al. 3-month formulation of goserelin acetate (‘Zoladex’ 10.8-mg depot) in advanced prostate cancer: results from an Italian, open, multicenter trial. Urol Int. 2003; 70: 316–320.
Alloul K, Sauriol L, Lafortune L. Meta-analysis and economic evaluation of LH-RH agonists' depot formulations in advanced prostatic carcinoma. Can J Urol. 1998; 5: 585–594.
Garnick MB, Fair W. Combating prostate cancer. Sci Am. 1998; 279: 74–83.
Thompson IM, Zeidman EJ, Rodriguez FR. Sudden death due to disease flare with leutenizing hormone-releasing hormone agonist therapy for carcinoma of the prostate. J Urol. 1990; 144: 1479–1480.
Schulze H, Senge T. Influence of different types of antiandrogens on leutenizing hormone-releasing hormone analogue induced testos-terone surge in patients with metastatic carcinoma of the prostate. J Urol. 1990; 144: 934–941.
Cook T, Sheridan WP. Development of GnRH antagonists for prostate cancer: new approaches to treatment. Oncologist. 2000; 5: 162–168.
Stricker HJ. Leutenizing hormone-releasing hormone antagonists in prostate cancer. Urology. 2001; 58: 24–27.
Tomera K, Gleason D, Gittelman M, et al. The gonadotropin-releasing hormone antagonist abarelix depot versus luteinizing hormone releasing hormone agonists leuprolide or goserelin: initial results of endocrinological and biochemical efficacies in patients with prostate cancer. J Urol. 2001; 165: 1585–1589.
McLeod D, Zinner N, Tomera K, et al. A phase 3, multicenter, open-label, randomized study of abarelix versus leuprolide acetate in men with prostate cancer. Urology. 2001; 58: 756–761.
Hausberger AG, DeLuca PP. Characterization of biodegradable poly( D,L -lactide-co-glycolide) polymers and microspheres. J Pharm Biomed Anal. 1995; 13: 747–760.
Couvreur P, Blanco-Prieto MJ, Puisieux F, Roques B, Fattal E. Multiple emulsion technology for the design of microspheres containing peptides and oligopeptides. Adv Drug Deliv Rev. 1997; 28: 85–96.
Mehta RC, Jeyanthi R, Calis S, Thanoo BC, Burton KW, DeLuca PP. Biodegradable microspheres as depot system for parenteral delivery of peptide drugs. J Control Release. 1994; 29: 375–384.
Woo BH, Kostanski JW, Gebrekidan S, Dani BA, Thanoo BC, DeLuca PP. Preparation, characterization and in vivo evaluation of 120-day poly( D,L -lactide) leuprolide microspheres. J Control Release. 2001; 75: 307–315.
Kostanski JW, Thanoo BC, DeLuca PP. Preparation, characterization and in vitro evaluation of 1- and 4-month controlled release Orntide PLA and PLGA microspheres. Pharm Dev Technol. 2000; 5: 585–596.
Kostanski JW, Jiang G, Dani BA, Murty SB, Qin W, Schrier B, Thanoo BC, DeLuca PP. Return to fertility after extended chemical castration with a GnRH antagonist. BMC Cancer. 2001; 1: 18.
Atkinson A, Thompson SJ, Khan AT, et al. Assessment of a two-generation reproductive and fertility study of mercuric chloride in rats. Food Chem Toxicol. 2001; 39: 73–84.
McFarlane M, Price SC, Cottrell S, et al. Hepatic and associated response of rats to pregnancy, lactation and simultaneous treatment with butylated hydroxytoluene. Food Chem Toxicol. 1997; 35: 753–767.
Author information
Authors and Affiliations
Corresponding author
Additional information
Published: March 11, 2004
Rights and permissions
About this article
Cite this article
D'Souza, S.S., Selmin, F., Murty, S.B. et al. Assessment of fertility in male rats after extended chemical castration with a GnRH antagonist. AAPS J 6, 10 (2004). https://doi.org/10.1208/ps060110
Received:
Accepted:
Published:
DOI: https://doi.org/10.1208/ps060110