Equines Choriongonadotropin: Biologie und veterinärmedizinische Bedeutung

Zusammenfassung

Die hypophysären Gonadotropine follikelstimulierendes Hormon (FSH) und luteinisierendes Hormon (LH) spielen eine zentrale Rolle bei der Steuerung der Gonadenfunktionen. Daher ist ihr Einsatz in der Therapie von Fruchtbarkeitsstörungen (z. B. Azyklie) sowie in der Biotechnologie (z. B. Superovulation, Hormonprogramme zur Zyklussynchronisation) prinzipiell von hohem Interesse. Präparationen von FSH bzw. LH sind aufgrund der aufwendigen Gewinnung aus Hypophysengewebe relativ teuer und daher besonderen Anwendungen vorbehalten. Bei Primaten- und Equidenarten wurde die Expression eines LH-ähnlichen Moleküls im Chorionepithel nachgewiesen (Choriongonadotropin, CG). Equines CG (eCG) weist außer bei Equiden, bei denen es ausschließlich an LH-Rezeptoren bindet, bei allen bei uns üblichen Haussäugetierspezies neben seiner LH-Aktivität eine außerordentlich hohe FSH-Aktivität auf („duale Wirkung“). Seit seiner Markteinführung kommt ihm daher eine hohe Bedeutung als vergleichsweise kostengünstiges FSH-Analogon vorwiegend zur Anwendung bei Wiederkäuern und Schwein zu. Im Gegensatz zu dem als LH-Analogon eingesetzten humanen CG (hCG), das nicht invasiv aus dem Urin schwangerer Frauen isoliert werden kann, muss die Gewinnung von eCG aus dem Blut trächtiger Spenderstuten erfolgen, da im Urin nur minimale eCG-Konzentrationen vorliegen. Nach Berichten über Todesfälle und Leiden von Spenderstuten im Zusammenhang mit der eCG-Gewinnung in südamerikanischen Haltungen ist das derzeitige Verfahren der eCG-Produktion zunehmend in die öffentliche Kritik geraten, was zuletzt in Forderungen nach einem generellen Verbot mündete. Ziel dieses Beitrags ist daher, den aktuellen Kenntnisstand zu Eigenschaften und Biologie dieses auch aus Sicht der Grundlagenwissenschaft hochinteressanten Moleküls kurz zusammenzufassen.

Abstract

The pituitary gonadotrophins follicle-stimulating hormone (FSH) and luteinizing hormone (LH) play a prominent role in the control of gonadal functions. Therefore, their use in the treatment of fertility disorders (e. g. anovulatory anestrus) as well as in biotechnology (e. g. superovulation, hormone programs for cycle synchronization) is of substantial interest. Preparations of FSH or LH are relatively expensive due to the laborious extraction from pituitary tissue and are therefore reserved for special indications. In primates and equids, the chorionic epithelium expresses an LH-like molecule (chorionic gonadotrophin, CG). Equine CG (eCG) selectively binds to LH receptors in equids. In all other domestic mammalian species, equine CG (eCG) shows an extraordinarily high FSH activity in addition to its LH activity (“dual activity”). Since its market launch, this has therefore gained considerable importance as a comparatively inexpensive FSH analogue, mainly for use in ruminants and pigs. In contrast to the human CG (hCG), which may be isolated non-invasively from the urine of pregnant women and is widely used as LH analogue, eCG must be extracted from the blood of pregnant donor mares, as eCG concentrations in urine are only minimal. Following reports of deaths and suffering of donor mares associated with eCG collection in South American settings, the current practice of eCG production has given rise to increasing public criticism. This has recently led to calls for a general production ban. Primary aim of this review is therefore to summarize the current state of knowledge concerning the properties and biology of this molecule, which is also highly interesting from the point of view of basic science.

Schlüsselwörter

eCG - hCG - LH - FSH - endometrial cup

Key words

eCG - hCG - LH - FSH - endometrial cup

Publication History

Received: 20 February 2020

Accepted: 15 May 2020

Article published online:
20 October 2020

• Literatur

• 1 Palermo R. Differential actions of FSH and LH during folliculogenesis. Reproductive BioMedicine Online 2007; 15: 326-337
• 2 Mihm M, Evans AC. Mechanisms for dominant follicle selection in monovulatory species: a comparison of morphological, endocrine and intraovarian events in cows, mares and women. Reprod Domest Anim 2008; 43 (Suppl. 02) 48-56
• 3 Adams GP, Jaiswal R, Singh J. et al. Progress in understanding ovarian follicular dynamics in cattle. Theriogenology 2008; 69: 72-80
• 4 Adams GP, Singh J, Baerwald AR. Large animal models for the study of ovarian follicular dynamics in women. Theriogenology 2012; 78: 1733-1748
• 5 Niswender GD, Juengel JL, Silva PJ. et al. Mechanisms controlling the function and life span of the corpus luteum. Physiol Rev 2000; 80: 1-29
• 6 Ramaswamy S, Weinbauer GF. Endocrine control of spermatogenesis: Role of FSH and LH/testosterone. Spermatogenesis 2014; 4 (02) e996025
• 7 Zondek B. Über die Hormone des Hypophysenvorderlappens. Klin Wochenschr 1930; 9: 245-248
• 8 Fevold HL, Hisaw FL, Leonard SL. The gonad-stimulating and the luteinizing hormones from the anterior lobe of the hypophysis. Am J Physiol 1931; 97: 291-301
• 9 Lunenfeld B. Historical aspects in gonadotrophin therapy. Human Reprod Update 2004; 10: 453-467
• 10 Lunenfeld B, Bilger W, Longobardi S. et al. The development of gonadotropins for clinical use in the treatment of infertility. Front Endocrinol 2019; 10: 429
• 11 Bo GA, Mapletoft RJ. Historical perspectives and recent research on superovulation in cattle. Theriogenology 2014; 81: 38-48
• 12 Murphy BD, Martinuk SD. Equine chorionic gonadotropin. Endocr Rev 1991; 12: 27-44
• 13 Murphy BD. Equine chorionic gonadotropin: an enigmatic but essential tool. Anim Reprod 2012; 9: 223-230
• 14 De Rensis F, Lopez-Gatius F. Use of equine chorionic gonadotropin to control reproduction of the dairy cow: a review. Reprod Dom Anim 2014; 49: 177-182
• 15 Cole HH, Bigelow M, Finkel J. et al. Biological half-life of endogenous PMS following hysterectomy and studies on losses in urine and milk. Endocrinology 1967; 81: 927-930
• 16 Vilanova XM, De Briyne N, Beaver B. et al. Horse welfare during equine chorionic gonadotropin (eCG) production. Animals 2019; 9: 1053
• 17 Hoppen HO. The equine placenta and equine chorionic gonadotrophin. Exp Clin Endocrinol 1994; 102: 235-243
• 18 Allen WR. Fetomaternal interactions and influences during equine pregnancy. Reproduction 2001; 121: 513-527
• 19 Antczak DF, de Mestre AM, Wilsher S. et al. The equine endometrial cup reaction: a fetomaternal signal of significance. Annu Rev Anim Biosci 2013; 1: 419-442
• 20 Li MD, Ford JJ. A comprehensive evolutionary analysis based on nucleotide and amino acid sequences of the alpha- and beta-subunits of glycoprotein hormone gene family. J Endocrinol 1998; 156: 529-542
• 21 Mullen MP, Cooke DJ, Ceow MA. Structural and functional roles of FSH and LH as glycoproteins regulating reproduction in mammalian species. In: Vizcarra. ed. Gonadotropin. London, UK: InTech Open; 2013: 155-180
• 22 Jiang X, Dias JA, He X. Structural biology of glycoprotein hormones and their receptors: insight to signaling. Mol Cell Endocrinol 2014; 382: 424-451
• 23 Wide L, Eriksson K. Molecular size and charge as dimensions to identify and characterize circulating glycoforms of human FSH, LH and TSH. Ups J Med Sci 2017; 122: 217-223e
• 24 Watanabe N, Hatano J, Asahina K. et al. Molecular cloning and histological localization of LH-like substances in a bottlenose dolphin (Tursiops truncatus) placenta. Comp Biochem Physiol A Mol Integr Physiol 2007; 146: 105-118
• 25 Aschheim S, Zondek B. Hypophysenvorderlappenhormone und Ovarialhormone im Harn von Schwangeren. Klin Wochenschr 1927; 6: 13-21
• 26 Aschheim S, Zondek B. Das Hormon des Hypopysenvorderlappens: Testobjekt zum Nachweis des Hormons. Klin Wochenschr 1927; 6: 248-252
• 27 Cole HH, Hart GH. The potency of blood serum of mares in progressive stages of pregnancy in effecting the sexual maturity of the immature rat. Am J Physiol 1930; 93: 57-68
• 28 Merz WE. The primate placenta and human chorionic gonadotropin. Exp Clin Endocrinol 1994; 102: 222-234
• 29 Hallast P, Laan M. Evolution of the chorionic gonadotropin β genes in primates. In: Enzyclopedia of Life Sciences (ELS). Chichester: John Wiley & Sons Ltd; 2009: 1-9
• 30 Sherman GB, Wolfe MW, Farmerie TA. et al. A single gene encodes the β-subunits of equine luteinizing hormone and chorionic gonadotropin. Mol Endocrinol 1992; 6: 951-959
• 31 Chopineau M, Stewart F, Allen WR. Cloning and analysis of the cDNA encoding the horse and donkey luteinizing hormone beta-subunits. Gene 1995; 160: 253-256
• 32 Gospodarowicz D. Purification and physicochemical properties of the pregnant mare serum gonadotropin (PMSG). Endocrinology 1972; 91: 101-106
• 33 Roser JF, Papkoff H, Murthy HM. et al. Chemical, biological and immunological properties of pituitary gonadotropins from the donkey (Equus asinus): comparison with the horse (Equus caballus). Biol Reprod 1984; 30: 1253-1262
• 34 Smith PL, Bousfield GR, Kumar S. et al. Equine lutropin and chorionic gonadotropin bear oligosaccharides terminating with SO4–4-GalNAc and Sia alpha 2,3Gal, respectively. J Biol Chem 1993; 268: 795-802
• 35 Matsui T, Mizuochi T, Titani K. et al. Structural analysis of N-linked oligosaccharides of equine chorionic gonadotropin and lutropin beta-subunits. Biochemistry 1994; 33: 14039-14048
• 36 Legardinier S, Duonor-Cérutti M, Devauchelle G. et al. Biological activities of recombinant equine luteinizing hormone/chorionic gonadotropin (eLH/CG) expressed in Sf9 and Mimic insect cell lines. J Mol Endocrinol 2005; 34: 47-60
• 37 Ginther OJ, Pineda MH, Wentworth BC. et al. Rate of disappearance of exogenous LH from the blood in mares. J Anim Sci 1974; 39: 397-403
• 38 Catchpole HR, Cole HH, Pearson PB. Studies on the rate of disappearance and fate of mare gonadotrophic hormone following intravenous injection. Am J Physiol 1935; 112: 21-26
• 39 Cole HH, Bigelow M, Finkel J. et al. Biological half-life of endogenous PMS following hysterectomy and studies on losses in urine and milk. Endocrinology 1967; 81: 927-930
• 40 Saint-Dizier M, Foulon-Gauze F, Lecompte F. et al. Cloning and functional expression of the equine luteinizing hormone/chorionic gonadotrophin receptor. J Endocrinol 2004; 183: 551-559
• 41 Leiser R, Kaufmann P. Placental structure: in a comparative aspect. Exp Clin Endocrinol 1994; 102: 122-134
• 42 Allen WR, Hamilton DW, Moor RM. The origin of endometrial cups. II. Invasion of the endometrium by trophoblast. Anat Rec 1973; 177: 485-401
• 43 Wooding FBP, Morgan G, Fowden AL. et al. A structural and immunological study of chorionic gonadotrophin production by equine trophoblast girdle and cup cells. Placenta 2001; 22: 749-767
• 44 Allen WR, Wilsher S. A review of implantation and early placentation in the mare. Placenta 2009; 30: 1005-1015
• 45 Hoffmann B, Gentz F, Failing K. Investigations into the course of progesterone-, oestrogen- and eCG-concentrations during normal and impaired pregnancy in the mare. Reprod Domest Anim 1996; 32: 717-723
• 46 Schauder W. Untersuchungen über die Eihäute und Embryotrophe des Pferdes. Arch Anat Physiol 1912; 192: 259-302
• 47 Cole HH, Goss H. The source of equine gonadotrophin. In: Essays in honour of Herbert M. Evans. Berkeley: University of California Press; 1943: 107-119
• 48 Allen WR, Moor RM. The origin of the equine endometrial cups. I. Production of PMSG by fetal trophoblast cells. J Reprod Fertil 1972; 29: 313-316
• 49 McNeilly AS, Crawford JL, Taragnat C. et al. The differential secretion of FSH and LH: regulation through genes, feedback and packaging. Reproduction Suppl 2013; 61: 463-476
• 50 Duran-Pasten ML, Fiordelisio T. GnRH-induced Ca2 + signaling patterns and gonadotropin secretion in pituitary gonadotrophs. Functional adaptations to both ordinary and extraordinary physiological demands. Front Endocrinol (Lausanne) 2013; 4: 127
• 51 Stamatiades GA, Kaiser UB. Gonadotropin regulation by pulsatile GnRH: signaling and gene expression. Mol Cell Endocrinol 2018; 463: 131-141
• 52 Wilsher S, Allen WE. Factors influencing equine chorionic gonadotrophin production in the mare. Equine Vet J 2011; 43: 430-438
• 53 Brosnahan MM, Silvela EJ, Crumb J. et al. Ectopic trophoblast allografts in the horse resist destruction by secondary immune responses. Biol Reprod 2016; 95 (06) 135
• 54 Dokras A, Sargent IL, Ross C. et al. The human blastocyst: morphology and human chorionic gonadotropin secretion in vitro. Human Reprod 1991; 6: 1143-1151
• 55 Mihm M, Gangooly S, Muttukrishna S. The normal menstrual cycle in women. Anim Reprod Sci 2011; 124: 229-236
• 56 Bazer FW, Thatcher WW. Theory of maternal recognition of pregnancy in swine based on estrogen controlled endocrine versus exocrine secretion of prostaglandin F2alpha by the uterine endometrium. Prostaglandins 1977; 14: 397-400
• 57 Ziecik AJ, Przygrodzka E, Jalali BM. et al. Regulation of the porcine corpus luteum function. Reproduction 2018; 156: R57-R67
• 58 Ealy AD, Wooldridge LK. The evolution of interferon-tau. Reproduction 2017; 154: F1-F10
• 59 Klein C. Early pregnancy in the mare: old concepts revisited. Domest Anim Reprod 2016; 56 Suppl: S212-S217
• 60 Evans MJ, Irvine CH. Serum concentrations of FSH, LH and progesterone during the oestrous cycle and early pregnancy in the mare. J Reprod Fertil Suppl 1975; 23: 193-200
• 61 Urwin VE, Allen WR. Pitutary and chorionic gonadotrophic control of ovarian function during early pregnancy in equids. J Reprod Fertil Suppl 1982; 32: 371-381
• 62 Daels PF, Albrecht BA, Mohammed HO. Equine chorionic gonadotropin regulates luteal steroidogenesis in pregnant mares. Biol Reprod 1998; 59: 1062-1068
• 63 Holtan DW, Squires EL, Lapin DR. et al. Effect of ovariectomy on pregnancy in mares. J Reprod Fert Suppl 1979; 27: 457-463
• 64 Scholtz EL, Krishnan S, Ball BA. et al. Pregnancy without progesterone in horses defines a second endogenous biopotent progesterone receptor agonist, 5alpha-dihydroprogesterone. Proc Natl Acad Sci 2014; 111: 3365-3370
• 65 Conley AJ, Ball BA. Steroids in the establishment and maintenance of pregnancy and at parturition in the mare. Reproduction 2019; 158: R197-R208
• 66 Holtan DW, Houghton E, Silver M. et al. Plasma progestagens in the mare, fetus and newborn foal. J Reprod Fertil Suppl 1991; 44: 517-528
• 67 Fournier T, Guibourdenche J, Evain-Brion D. Review: hCGs: different sources of production, different glycoforms and functions. Placenta Suppl 1 2015; 36: 60-65
• 68 Schumacher A. Human chorionic gonadotropin as a pivotal endocrine immune regulator initiating and preserving fetal tolerance. Int J Mol Sci 2017; 18: 2166
• 69 Fields MJ, Schemesh M. Extragonadal luteinizing hormone receptors in the reproductive tract of domestic animals. Biol Reprod 2004; 71: 1412-1418
• 70 Ziecik AJ, Bodek G, Blitek A. et al. Nongonadal LH receptors, their involvement in female reproductive function and a new applicable approach. Vet J 2005; 169: 75-84
• 71 Gonzales-Mencio F, Manns J, Murphy BD. FSH and LH activity of PMSG from mares at different stages of gestation. Anim Reprod Sci 1978; 1: 137-144
• 72 Murphy BD, Mapletoft R, Manns J. et al. Variability in gonadotrophin preparations as a factor in the superovulatory response. Theriogenology 1984; 21: 117-125
• 73 Combarnous Y, Guillou F, Martinat N. Comparison of in vitro follicle-stimulating hormone (FSH) activity of equine gonadotropins (luteinizing hormone, FSH, and chorionic gonadotropin) in male and female rats. Endocrinology 1984; 115: 1821-1827
• 74 Menzer C, Schams D. Radioimmunoassay for PMSG and its application to in-vivo-studies. J Reprod Fert 1979; 55: 339-345
• 75 Hunter MG, Robinson RS, Mann GE. et al. Endocrine and paracrine control of follicular development and ovulation rate in farm species. Anim Reprod Sci 2004; 82–83: 461-477
• 76 Meinecke B, Meinecke-Tillmann S. Fertilität – die Perspektive der Eizelle. Tierärztl Prax Ausg G Grosstiere Nutztiere 2008; 36 (03) 213-217
• 77 Dieleman SJ, Bevers MM, Vos PLAM. et al. PMSG/anti-PMSG in cattle: a simple and efficient superovulatory treatment?. Theriogenology 1993; 39: 25-41
• 78 Cornejo-Cortés MA, Sánchez-Torres C, Vázquez-Chagoyán JC. et al. Rat embryo quality and production efficiency are dependent on gonadotrophin dose in superovulatory treatments. Lab Anim 2006; 40: 87-95
• 79 Luo C, Zuñiga J, Edison E. et al. Superovulation strategies for 6 commonly used mouse strains. J Am Assoc Lab Anim Sci 2011; 50: 471-478
• 80 Abecia JA, Forcada F, González-Bulnes A. Hormonal control of reproduction in small ruminants. Anim Reprod Sci 2012; 130: 173-179
• 81 De Rensis F, Kirkwood RN. Control of estrus and ovulation: fertility to timed insemination of gilts and sows. Theriogenology 2016; 86: 1460-1466
• 82 Chenault JR, Kratzer DD, Rzepkowski RA. et al. LH and FSH response of Holstein heifers to fertirelin acetate, gonadorelin and buserelin. Theriogenology 1990; 34: 81-98
• 83 Gong JG, Bramley TA, Gutierrez CG. et al. Effects of chronic treatment with a gonadotrophin-releasing hormone agonist on peripheral concentrations of FSH and LH, and ovarian function in heifers. J Reprod Fertil 1995; 105: 263-270
• 84 Kulick LJ, Bergfelt DR, Kot K. et al. Follicle selection in cattle: follicle deviation and codominance within sequential waves. Biol Reprod 2001; 65: 839-846
• 85 Ginther OJ, Bashir ST, Hoffman MM. et al. Endocrinology of number of follicular waves per estrous cycle and contralateral or ipsilateral relationship between corpus luteum and preovulatory follicle in heifers. Domest Anim Endocrinol 2013; 45: 64-71
• 86 Hesser MW, Morris JC, Gibbons JR. Advances in recombinant gonadotropin production for use in bovine superovulation. Reprod Dom Anim 2011; 46: 933-942
• 87 Schneider F, Tomek W, Gründker C. Gonadotropin-releasing hormone (GnRH) and its natural analogues: A review. Theriogenology 2006; 66: 691-709
• 88 Kauffold J, Schneider F, Zaremba W. et al. Lamprey GnRH-lll stimulates FSH secretion in barrows. Reprod Dom Anim 2005; 40: 475-479
• 89 Kovacs M, Seprodi J, Koppan M. et al. Lamprey gonadotropin hormone-releasing hormone-III has no selective follicle-stimulating hormone-releasing effect in rats. J Neuroendocrinol 2002; 14: 647-655
• 90 Brüssow K-P, Schneider F, Tuchscherer A. et al. Influence of synthetic lamprey GnRH-III in gonadotropin release and steroid hormone levels in gilts. Theriogenology 2010; 74: 1570-1578
• 91 Amstalden M, Zieba DA, Garcia MR. et al. Evidence that lamprey GnRH-III does not release FSH selectively in cattle. Reproduction 2004; 127: 35-43
• 92 Thotakura NR, Blithe DL. Glycoprotein hormones: glycobiology of gonadotrophins, thyrotrophin and free alpha subunit. Glycobiology 1995; 5: 3-10
• 93 Legardinier S, Cahoreau C, Klett D. et al. Involvement of equine chorionic gonadotropin (eCG) carbohydrate side chains in its bioactivity; lessons from recombinant hormone expressed in insect cells. Reprod Nutr Dev 2005; 45: 255-259
• 94 Loumaye E, Martineau I, Piazzi A. et al. Clinical assessment of human gonadotrophins produced by recombinant DNA technology. Human Reprod 1996; 11 (Suppl. 01) 95-107
• 95 Alvarez RH, Natal FL, Ribela MT. et al. Physical-chemical and biological characterization of different preparations of equine chorionic gonadotropin. J Vet Sci 2016; 17: 459-465
• 96 Adams TE, Boime I. The expanding role of recombinant gonadotropins in assisted reproduction. Reprod Domest Anim 2008; 43 (Suppl. 02) 186-192
• 97 Galet C, Guillou F, Foulon-Gauze F. et al. The beta104–109 sequence is essential for the secretion of correctly folded single-chain beta alpha horse LH/CG and for its FSH activity. J Endocrinol 2009; 203: 167-174
• 98 Rutigliano HM, Adams BM, Jablonka-Shariff A. et al. Effect of single-chain ovine gonadotropins with dual activity on ovarian function in sheep. Reproduction 2014; 148: 129-136
• 99 Gifre L, Arís A, Bach À. et al. Trends in recombinant protein use in animal production. Microb Cell Fact 2017; 16: 40
• 100 Bellow RA, Staigmiller RB, Wilson JM. et al. Use of bovine FSH for superovulation and embryo production in beef heifers. Theriogenology 1991; 35: 1069-1082
• 101 Wilson JM, Jones AL, Moore K. et al. Superovulation of cattle with a recombinant-DNA bovine follicle stimulating hormone. Anim Reprod Sci 1993; 33: 71-82
• 102 Crowe MA, Enright WJ, Boland MP. et al. Follicular growth and serum follicle-stimulating hormone (FSH) responses to recombinant bovine FSH in GnRH-immunized anoestrous heifers. Anim Sci (Penicuik, Scotland) 2001; 73: 115-122
• 103 Carvalho PD, Hackbart KS, Bender RW. et al. Use of a single injection of long-acting recombinant bovine FSH to superovulate Holstein heifers: A preliminary study. Theriogenology 2014; 82: 481-489