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

The spatio-temporal distribution of aromatase cytochrome in ovary throughout the canine oestrous cycle

L. Lindh https://orcid.org/0000-0001-8381-789X A * , M. P. Kowalewski B , S. K. Goericke-Pesch C , H. Lindeberg D , G. Schuler E and O. A. T. Peltoniemi A
+ Author Affiliations
- Author Affiliations

A Department of Production Animal Medicine, University of Helsinki, Saarentaus FI-04920, Finland.

B University of Zürich, Institute of Veterinary Anatomy, Vetsuisse Faculty, Winterthurerstrasse 260, Zurich 8057, Switzerland.

C Reproductive Unit – Clinic for Small Animals, University of Veterinary Medicine Hannover, Hannover, Germany.

D Natural Resources Institute Finland (Luke), Production Systems, Halolantie 31 A, Maaninka FI-71750, Finland.

E Veterinary Clinic for Obstetrics, Gynecology and Andrology, Justus Liebig University, Giessen, Germany.

* Correspondence to: lena.lindh@helsinki.fi

Handling Editor: Jennifer Juengel

Reproduction, Fertility and Development 36, RD23201 https://doi.org/10.1071/RD23201
Submitted: 29 October 2023  Accepted: 16 February 2024  Published online: 15 March 2024

© 2024 The Author(s) (or their employer(s)). Published by CSIRO Publishing

Abstract

Context

New animal welfare legislation and ethical guidelines encourage alternative approaches for canine contraception, instead of surgical gonadectomy which is considered invasive and unjustified in healthy dogs.

Aims

Reversible contraception might be achieved by inhibition of aromatase (CYP19), an enzyme catalysing the conversion of androgens to oestrogens. This study provides insights into the spatio-temporal expression and distribution of aromatase in canine ovarian tissue.

Methods

Ovarian tissue was collected from 39 healthy and sexually mature bitches during different stages of the oestrous cycle: pro-oestrus (n = 8), oestrus (n = 12), dioestrus (n = 9) (luteal phase) and anoestrus (n = 10). Localisation of cytochrome P450 aromatase was determined by immunohistochemistry.

Key results

Aromatase activity in the dog is high during pro-oestrus, ovulation and early dioestrus. Comparing types of follicles and corpora lutea, the highest aromatase abundance was found in antral follicles and luteinising follicles, whereas corpora lutea and early antral follicles showed an intermediate presence of the enzyme. Interesting was the high abundance of aromatase in luteinising theca interna cells, prevailing over granulosa cells.

Conclusions and implications

Understanding of cells involved in oestradiol production is important for targeted inhibition of oestradiol synthesis, possibly offering an approach for contraception and suppression of oestrus.

Keywords: contraception, corpus luteum, endocrinology, folliculogenesis, granulosa cell, oestrogen, ovary, theca cell.

References

Abhilasha , Krishna A (1998) Immunolocalization of cytochrome P450 side chain cleavage, 17-alpha-hydroxylase and aromatase in the ovary of vespertilionid bat (Scotophilus heathi) during different phases of ovulatory delay. Biological Research 31(1), 49-57.
| Google Scholar | PubMed |

Ahokoski O, Irjala K, Taalikka M, Manninen P, Halonen K, Kangas L, Salminen E, Huupponen R, Scheinin H (2001) Pharmacokinetics of finrozole (MPV-2213ad), a novel selective aromatase inhibitor, in healthy men. British Journal of Clinical Pharmacology 52, 702-704.
| Crossref | Google Scholar | PubMed |

Araki H, Tsubota T, Maeda N, Harada N, Kominami S, Mason JI, Kita I (1996) Intraovarian immunolocalization of steroidogenic enzymes in a Hokkaido brown bear, Ursus arctos yesoensis during the mating season. Journal of Veterinary Medical Science 58(8), 787-790.
| Crossref | Google Scholar | PubMed |

Berky AGV, Townsend WL (1993) The relationship between the prevalence of uterine lesions and the use of medroxyprogesterone acetate for canine population control. Australian Veterinary Journal 70, 249-250.
| Crossref | Google Scholar | PubMed |

Carson RS, Richards JS, Kahn LE (1981) Functional and morphological differentiation of theca and granulosa cells during pregnancy in the rat: dependence on increased basal luteinizing hormone activity. Endocrinology 109, 1433-1441.
| Crossref | Google Scholar | PubMed |

Chang A-M, Chen C-C, Lee J-W, Hou D-L, Huang H-H, Ke G-M (2023) Effects of a novel recombinant gonadotropin-releasing hormone-1 vaccine on the reproductive function of mixed-breed dogs (Canis familiaris) in Taiwan. Vaccine 41(13), 2214-2223.
| Crossref | Google Scholar | PubMed |

Concannon PW (2009) Endocrinologic control of normal canine ovarian function. Reproduction in Domestic Animals 44(s2), 3-15.
| Crossref | Google Scholar |

Concannon PW (2011) Reproductive cycles of the domestic bitch. Animal Reproduction Science 124(3–4), 200-210.
| Crossref | Google Scholar | PubMed |

Concannon PW, Hansel W, Visek WJ (1975) The ovarian cycle of the bitch: plasma estrogen, LH and progesterone. Biology of Reproduction 13, 112-121.
| Crossref | Google Scholar | PubMed |

Donovan CE, Greer M, Kutzler MA (2012) Physiologic responses following gonadotropin-releasing hormone immunization in intact male dogs. Reproduction in Domestic Animals 47(s6), 403-405.
| Crossref | Google Scholar |

Drummond AE (2006) The role of steroids in follicular growth. Reproductive Biology and Endocrinology 4, 16.
| Crossref | Google Scholar | PubMed |

el-Maasarany S, Brandt ME, Majercik MH, Zimniski SJ, Puett D (1991) Immunocytochemical localization and enzymatic distribution of rat ovarian aromatase. Biology of Reproduction 44, 550-560.
| Crossref | Google Scholar | PubMed |

Fontaine E, Mir F, Vannier F, Albouy M, Fontbonne A (2011) Use of anti-oestrogens and aromatase inhibitors to prevent heat induction in anoestrous bitches treated with deslorelin implants. Reproduction in Domestic Animals 46(Suppl. 3), 105.
| Google Scholar |

Gonzalez G, Guendulain C, Maffrand C, Gobello C (2009) Comparison of the effect of the aromatase inhibitor, anastrazole, to the antioestrogen, tamoxifen citrate, on canine prostate and semen. Reproduction in Domestic Animals 44, 316-319.
| Crossref | Google Scholar | PubMed |

Hart BL, Hart LA, Thigpen AP, Willits NH (2014) Long-term health effects of neutering dogs: comparison of labrador retrievers with golden retrievers. PLoS ONE 9, e102241.
| Crossref | Google Scholar | PubMed |

Hart BL, Hart LA, Thigpen AP, Willits NH (2016) Neutering of German Shepherd Dogs: associated joint disorders, cancers and urinary incontinence. Veterinary Medicine and Science 2, 191-199.
| Crossref | Google Scholar | PubMed |

Hoffmann B, Kyrein HJ, Ender ML (1973) An efficient procedure for the determination of progesterone by radioimmunoassay applied to bovine peripheral plasma. Hormone Research 4(5), 302-310.
| Crossref | Google Scholar | PubMed |

Hoffmann B, Höveler R, Hasan SH, Failing K (1992) Ovarian and pituitary function in dogs after hysterectomy. Journal of Reproduction and Fertility 96(2), 837-845.
| Crossref | Google Scholar | PubMed |

Hoffmann B, Höveler R, Nohr B, Hasan SH (1994) Investigations on hormonal changes around parturition in the dog and the occurrence of pregnancy-specific non conjugated oestrogens. Experimental and Clinical Endocrinology & Diabetes 102(3), 185-189.
| Crossref | Google Scholar | PubMed |

Hoffmann B, Büsges F, Engel E, Kowalewski MP, Papa P (2004) Regulation of corpus luteum-function in the bitch. Reproduction in Domestic Animals 39, 232-240.
| Crossref | Google Scholar | PubMed |

Hsueh AJW, Adashi EY, Jones PBC, Welsh TH, Jr (1984) Hormonal regulation of the differentiation of cultured ovarian granulosa cells. Endocrine Reviews 5(1), 76-127.
| Crossref | Google Scholar | PubMed |

Jöchle W, Andersen AC (1977) The estrous cycle in the dog: a review. Theriogenology 7(3), 113-140.
| Crossref | Google Scholar | PubMed |

Jurczak A, Janowski T, Zdunczyk S, Failing K, Schuler G, Hoffmann B (2020) Attempts to downregulate ovarian function in the bitch by applying a GnRH agonist implant in combination with a 3ß-hydroxysteroid-dehydrogenase blocker; a pilot study. Theriogenology 145, 176-180.
| Crossref | Google Scholar | PubMed |

Kim HH, Yeon SC, Houpt KA, Lee HC, Chang HH, Lee HJ (2006) Effects of ovariohysterectomy on reactivity in German Shepherd dogs. The Veterinary Journal 172, 154-159.
| Crossref | Google Scholar | PubMed |

Klein R, Schams D, Failing K, Hoffmann B (2003) Investigations on the re-establishment of the positive feedback of oestradiol during anoestrus in the bitch. Reproduction in Domestic Animals 38(1), 13-20.
| Crossref | Google Scholar | PubMed |

Knapp DW, Glickman NW, DeNicola DB, Bonney PL, Lin TL, Glickman LT (2000) Naturally-occurring canine transitional cell carcinoma of the urinary bladder A relevant model of human invasive bladder cancer. Urologic Oncology: Seminars and Original Investigations 5(2), 47-59.
| Crossref | Google Scholar | PubMed |

Kowalewski MP (2014) Luteal regression vs. prepartum luteolysis: regulatory mechanisms governing canine corpus luteum function. Reproductive Biology 14(2), 89-102.
| Crossref | Google Scholar | PubMed |

Kowalewski MP (2018) Selected comparative aspects of canine female reproductive physiology. In ‘Encyclopedia of reproduction’. (Ed. MK Skinner) pp. 682–691. (Elsevier) doi:10.1016/B978-0-12-809633-8.20527-X

Kowalewski MP, Mason JI, Howie AF, Morley SD, Schuler G, Hoffmann B (2006a) Characterization of the canine 3β-hydroxysteroid dehydrogenase and its expression in the corpus luteum during diestrus. The Journal of Steroid Biochemistry and Molecular Biology 101(4–5), 254-262.
| Crossref | Google Scholar | PubMed |

Kowalewski MP, Schuler G, Taubert A, Engel E, Hoffmann B (2006b) Expression of cyclooxygenase 1 and 2 in the canine corpus luteum during diestrus. Theriogenology 66(6–7), 1423-1430.
| Crossref | Google Scholar | PubMed |

Kowalewski MP, Ihle S, Siemieniuch MJ, Gram A, Boos A, Zduńczyk S, Fingerhut J, Hoffmann B, Schuler G, Jurczak A, Domosławska A, Janowski T (2015) Formation of the early canine CL and the role of prostaglandin E2 (PGE2) in regulation of its function: an in vivo approach. Theriogenology 83(6), 1038-1047.
| Crossref | Google Scholar | PubMed |

Kutzler M, Wood A (2006) Non-surgical methods of contraception and sterilization. Theriogenology 66, 514-525.
| Crossref | Google Scholar | PubMed |

Kutzler MA, Mohammed HO, Lamb SV, Meyers-Wallen VN (2003) Accuracy of canine parturition date prediction from the initial rise in preovulatory progesterone concentration. Theriogenology 60(6), 1187-1196.
| Crossref | Google Scholar | PubMed |

Langoi D, Pavone ME, Gurates B, Chai D, Fazleabas A, Bulun SE (2013) Aromatase inhibitor treatment limits progression of peritoneal endometriosis in baboons. Fertility and Sterility 99(3), 656-662.e3.
| Crossref | Google Scholar | PubMed |

Laurincik J, Kolodzieyski L, Hyttel P, Osawa Y, Niemann H, Schmoll F, Brem G, Schellander K (1996) Granulosa-cumulus-corona expansion and aromatase localization in preovulatory follicles in superovulated heifers. Acta Veterinaria Scandinavica 37, 99-107.
| Crossref | Google Scholar | PubMed |

Lautincik J, Kolodzieyski L, Elias V, Hyttel P, Osawa Y, Sirotkin A (1994) Immunocytochemical localization of aromatase in the ovary of superovulated cattle, pigs and sheep. Acta Veterinaria Scandinavica 35, 185-191.
| Crossref | Google Scholar |

Li X, Zhang H, Sheng X, Li B, Zhou J, Xu M, Weng Q, Watanabe G, Taya K (2012) Immunoreactivities of androgen receptor, estrogen receptors, p450arom, p450c17 proteins in wild ground squirrels ovaries during the nonbreeding and breeding seasons. Journal of Ovarian Research 5, 26.
| Crossref | Google Scholar | PubMed |

Lindh L, Lindeberg H, Banting A, Banting S, Sainmaa S, Beasley S, Korhonen HT, Peltoniemi OAT (2020) Administration of aromatase inhibitor MPV-2213ad to blue fox vixens (Vulpes lagopus) as a model for contraception in female dogs. Theriogenology 152, 53-63.
| Crossref | Google Scholar | PubMed |

Lindh L, Kowalewski MP, Günzel-Apel A-R, Goericke-Pesch S, Myllys V, Schuler G, Dahlbom M, Lindeberg H, Peltoniemi OAT (2023) Ovarian and uterine changes during the oestrous cycle in female dogs. Reproduction, Fertility and Development 35(4), 321-337.
| Crossref | Google Scholar | PubMed |

Liu Y, Tian Y, Zhao X, Jiang S, Li F, Zhang Y, Zhang X, Li Y, Zhou J, Fang F (2015) Immunization of dogs with recombinant GnRH-1 suppresses the development of reproductive function. Theriogenology 83(3), 314-319.
| Crossref | Google Scholar | PubMed |

Maenhoudt C, Santos NR, Fontbonne A (2018) Manipulation of the oestrous cycle of the bitch—what works… for now. Reproduction in Domestic Animals 53(S3), 44-52.
| Crossref | Google Scholar |

Mlodawska W, Slomczynska M (2010) Immunohistochemical localization of aromatase during the development and atresia of ovarian follicles in prepubertal horses. Theriogenology 74, 1707-1712.
| Crossref | Google Scholar | PubMed |

Onclin K, Murphy B, Verstegen JP (2002) Comparisons of estradiol, LH and FSH patterns in pregnant and nonpregnant beagle bitches. Theriogenology 57, 1957-1972.
| Crossref | Google Scholar | PubMed |

Papa PC, Hoffmann B (2011) The corpus luteum of the dog: source and target of steroid hormones? Reproduction in Domestic Animals 46, 750-756.
| Crossref | Google Scholar | PubMed |

Pavone ME, Bulun SE (2013) The use of aromatase inhibitors for ovulation induction and superovulation. The Journal of Clinical Endocrinology & Metabolism 98(5), 1838-1844.
| Crossref | Google Scholar | PubMed |

Perez JF, Conley AJ, Dieter JA, Sanz-Ortega J, Lasley BL (1999) Studies on the origin of ovarian interstitial tissue and the incidence of endometrial hyperplasia in domestic and feral cats. General and Comparative Endocrinology 116(1), 10-20.
| Crossref | Google Scholar |

Reichler IM (2009) Gonadectomy in cats and dogs: a review of risks and benefits. Reproduction in Domestic Animals 44, 29-35.
| Crossref | Google Scholar | PubMed |

Reichler IM, Hung E, Jöchle W, Piché CA, Roos M, Hubler M, Arnold S (2005) FSH and LH plasma levels in bitches with differences in risk for urinary incontinence. Theriogenology 63, 2164-2180.
| Crossref | Google Scholar | PubMed |

Root Kustritz MV (2012) Managing the reproductive cycle in the bitch. Veterinary Clinics of North America: Small Animal Practice 42(3), 423-437.
| Crossref | Google Scholar | PubMed |

Ru G, Terracini B, Glickman LT (1998) Host related risk factors for canine osteosarcoma. The Veterinary Journal 156(1), 31-39.
| Crossref | Google Scholar | PubMed |

Rucker HR, Parker MR (2022) Decreased attractivity in female garter snakes treated with an aromatase inhibitor. Journal of Experimental Zoology Part A: Ecological and Integrative Physiology 337(2), 171-180.
| Crossref | Google Scholar | PubMed |

Sasano H, Okamoto M, Mason JI, Simpson ER, Mendelson CR, Sasano N, Silverberg SG (1989) Immunolocalization of aromatase, 17α-hydroxylase and side-chain-cleavage cytochromes P-450 in the human ovary. Journal of Reproduction and Fertility 85, 163-169.
| Crossref | Google Scholar | PubMed |

Schäfer-Somi S, Kaya D, Aslan S (2022) Prepubertal use of long-term GnRH agonists in dogs: current knowledge and recommendations. Animals 12(17), 2267.
| Crossref | Google Scholar | PubMed |

Simpson ER, Davis SR (2001) Minireview: aromatase and the regulation of estrogen biosynthesis—some new perspectives. Endocrinology 142(11), 4589-4594.
| Crossref | Google Scholar | PubMed |

Slauterbeck JR, Pankratz K, Xu KT, Bozeman SC, Hardy DM (2004) Canine ovariohysterectomy and orchiectomy increases the prevalence of ACL injury. Clinical Orthopaedics and Related Research 429, 301-305.
| Crossref | Google Scholar |

Smith JT, Clarke IJ (2010) Seasonal breeding as a neuroendocrine model for puberty in sheep. Molecular and Cellular Endocrinology 324, 102-109.
| Crossref | Google Scholar | PubMed |

Songsasen N, Fickes A, Pukazhenthi BS, Wildt DE (2009) Follicular morphology, oocyte diameter and localisation of fibroblast growth factors in the domestic dog ovary. Reproduction in Domestic Animals 44(s2), 65-70.
| Crossref | Google Scholar |

Soto FRM, Ferreira F, Pinheiro SR, Nogari F, Risseto MR, de Souza O, Amaku M (2005) Adoption of shelter dogs in a Brazilian community: assessing the caretaker profile. Journal of Applied Animal Welfare Science 8, 105-116.
| Crossref | Google Scholar | PubMed |

Spanel-Borowski K (1981) Morphological investigations on follicular atresia in canine ovaries. Cell and Tissue Research 214, 155-168.
| Crossref | Google Scholar |

Stocco C (2008) Aromatase expression in the ovary: hormonal and molecular regulation. Steroids 73(5), 473-487.
| Crossref | Google Scholar | PubMed |

Takayama K, Fukaya T, Sasano H, Funayama Y, Suzuki T, Takaya R, Wada Y, Yajima A (1996) Immunohistochemical study of steroidogenesis and cell proliferation in polycystic ovarian syndrome. Human Reproduction 11(7), 1387-1392.
| Crossref | Google Scholar | PubMed |

Urfer SR, Kaeberlein M (2019) Desexing dogs: a review of the current literature. Animals 9(12), 1086.
| Crossref | Google Scholar | PubMed |

Valtonen M, Jalkanen L (1993) Species-specific features of oestrus development and blastogenesis in domestic canine species. Journal of Reproduction and Fertility 47, 133-137.
| Google Scholar | PubMed |

Wang Y, Wang Z, Yu W, Sheng X, Zhang H, Han Y, Yuan Z, Weng Q (2018) Seasonal expressions of androgen receptor, estrogen receptors and cytochrome P450 aromatase in the uteri of the wild Daurian ground squirrels (Spermophilus dauricus). European Journal of Histochemistry 62, 2889.
| Crossref | Google Scholar | PubMed |