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Reproduction, Fertility and Development Reproduction, Fertility and Development Society
Vertebrate reproductive science and technology
RESEARCH ARTICLE

Effect of vehicle and route of administration of letrozole on ovarian function in a bovine model

M. J. Yapura A , R. J. Mapletoft B , R. A. Pierson C , J. Singh A and G. P. Adams A D
+ Author Affiliations
- Author Affiliations

A Department of Veterinary Biomedical Sciences, Western College of Veterinary Medicine, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5B4, Canada.

B Department of Large Animal Clinical Sciences, Western College of Veterinary Medicine, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5B4, Canada.

C Department of Obstetrics, Gynecology and Reproductive Sciences, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan S7N 0W8, Canada.

D Corresponding author. Email: gregg.adams@usask.ca

Reproduction, Fertility and Development 26(8) 1198-1205 https://doi.org/10.1071/RD13100
Submitted: 22 March 2013  Accepted: 1 October 2013   Published: 1 November 2013

Abstract

The objective of this study was to determine the effects of vehicle and route of administration of letrozole on ovarian function in sexually mature beef heifers. On Day 3 (Day 0 = ovulation), heifers were assigned randomly to four treatment groups and given 1 mg kg–1 letrozole intravenously (iv, n = 10) or intramuscularly (im, n = 10) or given a placebo iv (control iv, n = 5) or im (control im, n = 5). The interwave interval was longer in heifers treated with letrozole im than in im and iv controls (11.7 ± 0.30 vs 9.5 ± 0.50 and 10 ± 0.43, respectively; P < 0.05). Corpus luteum diameter profiles and plasma progesterone concentrations were greater (P < 0.03 and P < 0.05, respectively) in heifers treated with letrozole im compared with control im. Plasma oestradiol concentrations were lower in both letrozole-treated groups compared with controls (P ≤ 0.03). Plasma LH concentrations tended to be elevated at the time of wave emergence in heifers treated with letrozole im compared with other groups (group-by-day interaction, P = 0.06) and plasma FSH concentrations tended to be greater (P < 0.09) in heifers treated with letrozole by either route compared with a single control group. We conclude that intramuscular administration of letrozole in oil is a feasible route and vehicle for the development of a letrozole-based treatment protocol for herd synchronisation in cattle.

Additional keywords: aromatase inhibitor, bovine reproduction, oestradiol, ovarian synchronisation.


References

Adams, G. P., Kot, K., Smith, C. A., and Ginther, O. J. (1993). Selection of a dominant follicle and suppression of follicular growth in heifers. Anim. Reprod. Sci. 30, 259–271.
Selection of a dominant follicle and suppression of follicular growth in heifers.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK3sXit1Kjsbk%3D&md5=2f47ada1089dd01e504e3f4a7565e9fcCAS |

Andersson, A. M., and Skakkebaek, N. E. (1999). Exposure to exogenous oestrogens in food: possible impact on human development and health. Eur. J. Endocrinol. 140, 477–485.
Exposure to exogenous oestrogens in food: possible impact on human development and health.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK1MXktlCntb8%3D&md5=321c22d477f8f4b1e7b1af8b0d08e512CAS | 10366402PubMed |

Baracaldo, M. I., Martinez, M. F., Adams, G. P., and Mapletoft, R. J. (2000). Superovulatory response following transvaginal follicle ablation in cattle. Theriogenology 53, 1239–1250.
Superovulatory response following transvaginal follicle ablation in cattle.Crossref | GoogleScholarGoogle Scholar | 1:STN:280:DC%2BD3czpsFKitg%3D%3D&md5=a79350cd6dcede7fdbb303f875cf4edbCAS | 10832749PubMed |

Bedaiwy, M. A., Abdelaleem, M. A., Hussein, M., Mousa, N., Brunengraber, L. N., and Casper, R. F. (2011). Hormonal, follicular and endometrial dynamics in letrozole-treated versus natural cycles in patients undergoing controlled ovarian stimulation. Reprod. Biol. Endocrinol. 9, 83.
Hormonal, follicular and endometrial dynamics in letrozole-treated versus natural cycles in patients undergoing controlled ovarian stimulation.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3MXotVKktbs%3D&md5=9dce3aead2e08405b070a90ec8dcc2cbCAS | 21693028PubMed |

Beg, M. A., Bergfelt, D. R., Kot, K., and Ginther, O. J. (2002). Follicle selection in cattle: dynamics of follicular-fluid factors during development of follicle dominance. Biol. Reprod. 66, 120–126.
Follicle selection in cattle: dynamics of follicular-fluid factors during development of follicle dominance.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD38Xht1yktg%3D%3D&md5=b1e0fc5852b461765289c02cc41966ccCAS | 11751273PubMed |

Bergfelt, D. R., Lightfoot, K. C., and Adams, G. P. (1994). Ovarian synchronisation following ultrasound-guided transvaginal follicle ablation in heifers. Theriogenology 42, 895–907.
Ovarian synchronisation following ultrasound-guided transvaginal follicle ablation in heifers.Crossref | GoogleScholarGoogle Scholar |

Bergfelt, D. R., Smith, C. A., Adams, G. P., and Ginther, O. J. (1997). Surges of FSH during the follicular and early luteal phases of the oestrous cycle in heifers. Theriogenology 48, 757–768.
Surges of FSH during the follicular and early luteal phases of the oestrous cycle in heifers.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK2sXms1Shsr4%3D&md5=4b0f34e98c455b4df8b29f8c419ab1bbCAS | 16728169PubMed |

Bergfelt, D. R., Kulick, L. J., Kot, K., and Ginther, O. J. (2000). Follicular and hormonal response to experimental suppression of FSH during follicle deviation in cattle. Theriogenology 54, 1191–1206.
Follicular and hormonal response to experimental suppression of FSH during follicle deviation in cattle.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD3MXktV2hug%3D%3D&md5=aa809400626eeb5ddc6ab0c59cfea1d3CAS | 11192178PubMed |

Bleach, E. C. L., Glencross, R. G., Feist, S. A., Groome, N. P., and Knight, P. G. (2001). Plasma inhibin A in heifers: relationship with follicle dynamics, gonadotrophins and steroids during the oestrous cycle and after treatment with bovine follicular fluid. Biol. Reprod. 64, 743–752.
Plasma inhibin A in heifers: relationship with follicle dynamics, gonadotrophins and steroids during the oestrous cycle and after treatment with bovine follicular fluid.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD3MXhsVKjsLk%3D&md5=abc7bca0f4ec21f5f3f0def2eb99dd4bCAS |

Bo, G. A., Adams, G. P., Caccia, M., Martinez, M., Pierson, R. A., and Mapletoft, R. J. (1995a). Ovarian follicular-wave emergence after treatment with progestogen and oestradiol in cattle. Anim. Reprod. Sci. 39, 193–204.
Ovarian follicular-wave emergence after treatment with progestogen and oestradiol in cattle.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK2MXotVams74%3D&md5=0ce07ebdddaada44c749c541dd974bc8CAS |

Bo, G. A., Adams, G. P., Pierson, R. A., and Mapletoft, R. J. (1995b). Exogenous control of follicular-wave emergence in cattle. Theriogenology 43, 31–40.
Exogenous control of follicular-wave emergence in cattle.Crossref | GoogleScholarGoogle Scholar |

Bridges, P. J., Lewis, P. E., Wagner, W. R., and Inskeep, E. K. (1999). Follicular growth, oestrus and pregnancy after fixed-time insemination in beef cows treated with intravaginal progesterone inserts and oestradiol benzoate. Theriogenology 52, 573–583.
Follicular growth, oestrus and pregnancy after fixed-time insemination in beef cows treated with intravaginal progesterone inserts and oestradiol benzoate.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK1MXntlWjur0%3D&md5=cfa778dbbeeb97b46818e4f8423a7c7eCAS | 10734357PubMed |

Campbell, B. K., Picton, H. M., Mann, G. E., McNeilly, A. S., and Baird, D. T. (1991). Effect of steroid- and inhibin-free ovine follicular fluid on ovarian follicles and ovarian hormone secretion. J. Reprod. Fertil. 93, 81–96.
Effect of steroid- and inhibin-free ovine follicular fluid on ovarian follicles and ovarian hormone secretion.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK3MXmt1eqtLk%3D&md5=3a73c28cdb14c7a2cf652e0cbe6f8c8cCAS | 1920301PubMed |

Casper, R. F. (2003). Letrozole: ovulation or superovulation? Fertil. Steril. 80, 1335–1337.
Letrozole: ovulation or superovulation?Crossref | GoogleScholarGoogle Scholar | 14667863PubMed |

Casper, R. F. (2007). Aromatase inhibitors in ovarian stimulation. J. Steroid Biochem. Mol. Biol. 106, 71–75.
Aromatase inhibitors in ovarian stimulation.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD2sXhtVWitbbO&md5=210ba95f801520332e95dcef65079a5fCAS | 17604615PubMed |

Cohen, M. H., Johnson, J. R., Li, N., Chen, G., and Pazdur, R. (2002). Approval summary: letrozole in the treatment of postmenopausal women with advanced breast cancer. Clin. Cancer Res. 8, 665–669.
| 1:CAS:528:DC%2BD38XislOqt7o%3D&md5=c6e158ca3df530bbdaf9153e32fe8505CAS | 11895893PubMed |

Cortínez, A., De Carvalho, I., Vantman, D., Gabler, F., Iñiguez, G., and Vega, M. (2005). Hormonal profile and endometrial morphology in letrozole-controlled ovarian hyperstimulation in ovulatory infertile patients. Fertil. Steril. 83, 110–115.
Hormonal profile and endometrial morphology in letrozole-controlled ovarian hyperstimulation in ovulatory infertile patients.Crossref | GoogleScholarGoogle Scholar | 15652895PubMed |

Daxenberger, A., Ibarreta, D., and Meyer, H. H. D. (2001). Possible health impact of animal oestrogens in food. Hum. Reprod. Update 7, 340–355.
Possible health impact of animal oestrogens in food.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD3MXkt1Okurk%3D&md5=c9356960b4e800eb20b060136ff4f372CAS | 11392381PubMed |

Dedes, I. (2012). Kisspeptins and the control of gonadotrophin secretion. Syst. Biol. Reprod. Med. 58, 121–128.
Kisspeptins and the control of gonadotrophin secretion.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC38XntFyns7c%3D&md5=fa2cd8e15dede1b127735532272debdeCAS | 22376279PubMed |

Evans, A. C. O., Adams, G. P., and Rawlings, N. C. (1994). Endocrine and ovarian follicular changes leading up to the first ovulation in prepubertal heifers. J. Reprod. Fertil. 100, 187–194.
Endocrine and ovarian follicular changes leading up to the first ovulation in prepubertal heifers.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK2cXis1Wks7s%3D&md5=795e469b649a32883c8073d6ddf8045aCAS |

Fritsche, S., and Steinhart, H. (1999). Occurrence of hormonally active compounds in food: a review. Eur. Food Res. Technol. 209, 153–179.
Occurrence of hormonally active compounds in food: a review.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK1MXlsFSgtbY%3D&md5=345fe4cc1044aa176d5895589c519972CAS |

García-Galiano, D., Pinilla, L., and Tena-Sempere, M. (2012). Sex steroids and the control of the kiss1 system: developmental roles and major regulatory actions. J. Neuroendocrinol. 24, 22–33.
Sex steroids and the control of the kiss1 system: developmental roles and major regulatory actions.Crossref | GoogleScholarGoogle Scholar | 21951227PubMed |

Ginther, O. J., Kot, K., Kulick, L. J., and Wiltbank, M. C. (1997). Emergence and deviation of follicles during the development of follicular waves in cattle. Theriogenology 48, 75–87.
Emergence and deviation of follicles during the development of follicular waves in cattle.Crossref | GoogleScholarGoogle Scholar | 1:STN:280:DC%2BD28zgtVylsg%3D%3D&md5=69fa57cd48af4809e672b1c9b27d32c7CAS | 16728109PubMed |

Hafs, H. D., Louis, T. M., Noden, P. A., and Oxender, W. D. (1974). Control of the oestrous cycle with prostaglandin F2{alpha} in cattle and horses. J. Anim. Sci. 38, 10–21.

Health Canada (2005) ‘Drugs and Health Products. Veterinary Products. Questions and Answers: Hormonal Growth Promoters’. (Health Canada: Ottawa.) Available from http://www.hc-sc.gc.ca/dhp-mps/vet/faq/growth_hormones_promoters_croissance_hormonaux_stimulateurs-eng.php [Accessed 25th January, 2009].

Kastelic, J. P., Knopf, L., and Ginther, O. J. (1990). Effect of day of prostaglandin F2α treatment on selection and development of the ovulatory follicle in heifers. Anim. Reprod. Sci. 23, 169–180.
Effect of day of prostaglandin F treatment on selection and development of the ovulatory follicle in heifers.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK3MXisVWhsbk%3D&md5=e807323346ec86825db67461cd9df00eCAS |

Knopf, L., Kastelic, J. P., Schallenberger, E., and Ginther, O. J. (1989). Ovarian follicular dynamics in heifers: test of two-wave hypothesis by ultrasonically monitoring individual follicles. Domest. Anim. Endocrinol. 6, 111–119.
Ovarian follicular dynamics in heifers: test of two-wave hypothesis by ultrasonically monitoring individual follicles.Crossref | GoogleScholarGoogle Scholar | 1:STN:280:DyaL1M3nsFyitw%3D%3D&md5=f1c15441cf5771485b3ce03347c3a2b5CAS | 2659255PubMed |

Kulick, L. J., Kot, K., Wiltbank, M. C., and Ginther, O. J. (1999). Follicular and hormonal dynamics during the first follicular wave in heifers. Theriogenology 52, 913–921.
Follicular and hormonal dynamics during the first follicular wave in heifers.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK1MXns1Ohur4%3D&md5=cb7b000f5487531a010615263ef0b5b0CAS | 10735130PubMed |

Lane, E. A., Austin, E. J., and Crowe, M. A. (2008). Oestrous synchronisation in cattle – current options following the EU regulations restricting use of oestrogenic compounds in food-producing animals: a review. Anim. Reprod. Sci. 109, 1–16.
Oestrous synchronisation in cattle – current options following the EU regulations restricting use of oestrogenic compounds in food-producing animals: a review.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD1cXht12gu7%2FJ&md5=14eb614eee0c2ae39d28382c7a4d3f72CAS | 18786787PubMed |

Mapletoft, R. J., Martinez, M. F., Colazo, M. G., and Kastelic, J. P. (2003). The use of controlled internal drug release devices for the regulation of bovine reproduction. J. Anim. Sci. 81, E28–E36.

Martinez, M. F., Adams, G. P., Kastelic, J. P., Bergfelt, D. R., and Mapletoft, R. J. (2000). Induction of follicular wave emergence for estrus synchronization and artificial insemination in heifers. Theriogenology 54, 757–769.
Induction of follicular wave emergence for estrus synchronization and artificial insemination in heifers.Crossref | GoogleScholarGoogle Scholar | 1:STN:280:DC%2BD3M%2FovVGrtQ%3D%3D&md5=764c8616b5dc9845bf9a86ee52de5e91CAS | 11101036PubMed |

Mitwally, M. F., and Casper, R. F. (2001). Use of aromatase inhibitor for induction of ovulation in patients with an inadequate response to clomiphene citrate. Fertil. Steril. 75, 305–309.
Use of aromatase inhibitor for induction of ovulation in patients with an inadequate response to clomiphene citrate.Crossref | GoogleScholarGoogle Scholar | 1:STN:280:DC%2BD3M7ktlCgsg%3D%3D&md5=5a0cb7faa72ff761eee5f09714df99f8CAS | 11172831PubMed |

Mitwally, M. F., and Casper, R. F. (2002). Aromatase inhibition for ovarian stimulation: future avenues for infertility management. Curr. Opin. Obstet. Gynecol. 14, 255–263.
Aromatase inhibition for ovarian stimulation: future avenues for infertility management.Crossref | GoogleScholarGoogle Scholar | 12032380PubMed |

Murphy, K. G. (2005). Kisspeptins: Regulators of Metastasis and the Hypothalamic-Pituitary-Gonadal Axis. J. Neuroendocrinol. 17, 519–525.
Kisspeptins: Regulators of Metastasis and the Hypothalamic-Pituitary-Gonadal Axis.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD2MXmslCqs7w%3D&md5=3a3038dc4bc11a9bcb07eb8212eeac66CAS | 16011488PubMed |

Official Journal of the European Union (2003). Directive 2003/74/EC of the European Parliament and of the Council on 22 September 2003 amending Council Directive 96/22/EC concerning the prohibition on the use in stockfarming of certain substances having a hormonal or thyristatic action and of beta-agonist. pp. 17–21. (Publications Office of the European Union: Brussels.)

Peter, A. T., Levine, H., Drost, M., and Bergfelt, D. R. (2009). Compilation of classical and contemporary terminology used to describe morphological aspects of ovarian dynamics in cattle. Theriogenology 71, 1343–1357.
Compilation of classical and contemporary terminology used to describe morphological aspects of ovarian dynamics in cattle.Crossref | GoogleScholarGoogle Scholar | 1:STN:280:DC%2BD1Mzhs1Sksg%3D%3D&md5=e4c63c4afd704cb485e77a18d979ad77CAS | 19339040PubMed |

Pierson, R. A., and Ginther, O. J. (1987). Reliability of diagnostic ultrasonography for identification and measurement of follicles and detecting the corpus luteum in heifers. Theriogenology 28, 929–936.
Reliability of diagnostic ultrasonography for identification and measurement of follicles and detecting the corpus luteum in heifers.Crossref | GoogleScholarGoogle Scholar |

Rawlings, N. C., Jeffcoate, I. A., and Rieger, D. L. (1984). The influence of oestradiol-17[beta] and progesterone on peripheral serum concentrations of luteinising hormone and follicle-stimulating hormone in the ovariectomised ewe. Theriogenology 22, 473–488.
The influence of oestradiol-17[beta] and progesterone on peripheral serum concentrations of luteinising hormone and follicle-stimulating hormone in the ovariectomised ewe.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaL2MXhsl2ntA%3D%3D&md5=92da41c58d6516ab511cc120d6a455e2CAS | 16725980PubMed |

Requena, A., Herrero, J., Landeras, J., Navarro, E., Neyro, J. L., Salvador, C., Tur, R., Callejo, J., Checa, M. A., Farré, M., Espinós, J. J., Fábregues, F., Graña-Barcia, M., Reproductive Endocrinology Interest Group of Spanish Society of Fertility (2008). Use of letrozole in assisted reproduction: a systematic review and meta-analysis. Hum. Reprod. Update 14, 571–582.
Use of letrozole in assisted reproduction: a systematic review and meta-analysis.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD1cXht1Ois7%2FE&md5=673f9c2256e5dd1bc5efd50712f55f8cCAS | 18812422PubMed |

Umberger, E. J. (1975). Products marketed to promote growth in food-producing animals: steroid and hormone products. Toxicology 3, 3–21.
Products marketed to promote growth in food-producing animals: steroid and hormone products.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaE2MXosVCqtg%3D%3D&md5=578a086c3f978e51d8d93fda8f3d0482CAS | 1092030PubMed |

US Department of Agriculture Foreign Agricultural Service (2003). ‘Historic Overview and Chronology of EU’s Hormone Ban.’ GAIN Report E23206. (United States Department of Agriculture: Oklahoma.) Available from http://www.fas.usda.gov/scriptsw/attacherep/gain_display_report.asp?Rep_ID=145986773 [Verified 10 October 2013].

US Food and Drug Administration (2002). ‘The Use of Steroid Hormones for Growth Promotion in Food-Producing Animals.’ (Center for Veterinary Medicine: Silver Spring.) Available from http://www.fda.gov/cvm/hormones.htm [Accessed January 25th, 2009].

Whitlock, B. K. (2009) ‘Kisspeptin, a Novel Hypothalamic Regulator of the Somatotrophic and Gonadotrophic Axes in Ruminants.’ (Auburn University: Auburn.)

Yapura, J., Mapletoft, R. J., Pierson, R., Singh, J., Naile, J., Giesy, J. P., and Adams, G. P. (2011). A bovine model for examining the effects of an aromatase inhibitor on ovarian function in women. Fertil. Steril. 96, 434–438.e3.
A bovine model for examining the effects of an aromatase inhibitor on ovarian function in women.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3MXptlygs7o%3D&md5=d1cb757943b177459ab265ee4ff7594fCAS | 21696721PubMed |

Yapura, M. J., Mapletoft, R. J., Singh, J., Pierson, R., Naile, J., Giesy, J. P., Chang, H., Higley, E., Hecker, M., and Adams, G. P. (2012). Effects of a non-steroidal aromatase inhibitor on ovarian function in cattle. Reprod. Fertil. Dev. 24, 631–640.
Effects of a non-steroidal aromatase inhibitor on ovarian function in cattle.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC38XmtVKitbo%3D&md5=98bd7814cc9bb14cca58b4311e3eaf3dCAS | 22541551PubMed |