How much Follicle Stimulating Hormone do we really need for cattle superovulation ?

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Published on: January 3, 2020

Superovulation data

Although the American Embryo Transfer Association and the International Embryo Technology Society perform a tremendous and necessary review of embryo transfer activity in the United States (Tables 1 and 2) and worldwide, there are limited data available on the dose, type, route of delivery, and protocols for Follicle Stimulating Hormone (FSH) administration (Kelly, 1997).  Other factors that contribute to the success of ovarian hyperstimulation are the breed, age, parity, and management of cattle, ovarian follicular reserve, and superovulation history of a particular donor.  Delivery of FSH to achieve superovulation is generally a twice daily injection schedule beginning on the day before or the day of emergence of a follicular wave (Adams, 1992) and lasting for three or four days; however, single dose (Looney, 1986; Bo, 1994; Kelly, 1997) or split single dose delivery (Tribulo, 2012), as well as FSH gels (Kimura, 2016) and implants (Floyd, 2007) to enhance bioavailability have been reported.  The current FDA approved FSH product is a pituitary derivative although the interest in producing a custom, reliable, and effective, FSH (and Luteinizing Hormone [LH]) product from recombinant technology has a substantial history (Looney, 1988; Wilson, 1993) and is gaining considerable traction (Hesser, 2011; Vega, 2019).  Classically, pituitary-derived FSH products had substantial LH contamination and a role for each of the gonadotropins was hypothesized (Donaldson, 1985).  The current product is very pure although it is likely that some LH might well be important for successful nourishment of multiple dominant follicles (Ginther, 1996) although it may be difficult to mimic the pulsatile pattern of LH.  Regardless of the protocol, the most critical component for FSH administration is the timing relative to the endogenous FSH surge.  Practically, this approach requires a hormonal or mechanical technique to engineer a follicular wave in order to efficiently schedule the embryo collection (Crowe, 2013.  The protocol for engineering a follicular wave also has many considerations and challenges (time, expensive equipment, choice of hormones, etc.).

What if we miss an FSH injection?

The literature is scant with information about which FSH injections are the most important.  It seems logical that the first few injections are the most important (due to dosage and timing) and the last few are the least important.  Using a six FSH injection protocol following ultrasound guided follicular ablation of all follicles larger than 5 mm, the administration of the sixth FSH injection or not did not impact the embryo recovery results (Gibbons, 2019).  Practically, even if it is known that an FSH injection was missed, the donor will still likely be inseminated and embryo recovery attempted.  A single dose of FSH administered on Day 10 following estrus has been shown to produce a similar number of ovulations as a multi-dose approach (Kelly, 1997); however, there were more degenerate embryos and unfertilized ova, suggesting that in addition the scheduling aspect, engineering a follicular wave for superovulation may be important impact the “fertilizability” of the ova within the follicles and the timing of the first few FSH injections relative to follicular wave emergence outweighs the effects of any other single FSH injection.

FSH per Transferable Embryo

There is no public data base for the amount of FSH given to any one donor.  There are recent data (Gibbons, 2019) to suggest that the amount of FSH per transferable embryo may be as low as 1.5 mls (54 IU; Folltropin) following an engineered follicular wave.  The appropriate timing of FSH initiation could decrease the overall required dosage of FSH, which is financially important given that the cost of FSH is one of the largest single costs associated with superovulation.  Further, although there is a relatively accurate idea of how many corpora lutea (CL) are present at embryo collection, without counting the CL via ultrasonography, it is difficult to know if or how many embryos / ova are not accounted for following collection. 

Where do we go from here?

In vitro embryo technologies are clearly gaining considerable traction (Table 2.); however, the need for effective and efficient superovulation protocols remains important.  The effectiveness of these protocols is linked to the timing of the initial FSH injection; however, due to the considerable number of different protocols that are available it is difficult to determine which approach more appropriately exploits the endogenous FSH surge and results in more transferable embryos.  Future research comparing different FSH protocols relative to endogenous FSH profiles and follicular wave emergence will be important and may increase the number of transferable embryos per collection which has not waivered substantially in 20 plus years.

References:

Adams GP, Matteri RL, Kastelic JP, Ko JC, Ginther OJ.  Association between surges of follicle-stimulating hormone and the emergence of follicular waves in heifers.  Journal of Reproduction Fertility, 1992; 94(1):177-188.

Bo GA, Hockley DK, Nasser LF, Mapletoft RJ.  Superovulatory response to a single subcutaneous injection of Folltropin-V in beef cattle.  Theriogenology, 1994;42(6):963-975.

Crowe MA, Mullen MP.  Relative roles of FSH and LH in stimulation of effective follicular response in cattle.  Intech Open Access, 2013; http://dx.doi.org/10.5772/50272.

Donaldson LE.  LH and FSH at superovulation and embryo production in the cow.  Theriogenology 1985;23(3):441-447.

Floyd C.  Subcutaneous FSH implants.  MS Thesis, Clemson University, 2007: https://tigerprints.clemosn.edu/all_thesis/94.

Gibbons JR, Anton J.  Dominant follicle removal prior to superovulation.  Poster presented at 2019 joint annual AETA & CETA/ACTE convention, 2019.

Ginther OJ, Wiltbank MC, Fricke PM, Gibbons JR, Kot K.  Selection of the dominant follicle in cattle.  Biology of Reproduction 1996;55:1187-1194.

Hesser MW, Morris JC, Gibbons JR.  Advances in recombinant gonadotropin production for use in bovine superovulation.  Reproduction Domestic Animals, 2011;46:933-942.

Kelly P, Duffy P, Roche JF, Boland MP.  Superovulation in cattle: effect of FSH type and method of administration on follicular growth, ovulatory response and endocrine patterns.  Assisted Reproduction Sciences 1997;46:1-14.

Kimura K.  Superovulation with a single administration of FSH in aluminum hydroxide gel: a novel superovulation method for cattle.  Journal of Reproduction Development, 2016;62(5):423-429.

Looney CR, Bondioli KR, Hill KG, Massey JM.  Superovulation of donor cows with bovine follicle-stimulating hormone (bFSH) produced by recombinant DNA technology.  Theriogenology 1988;29:271.

Looney CR.  Superovulation in beef females.  Proceedings of the 5th annual conference of American Embryo Transfer Association, 1986;16-29.

Tribulo A, Rogan D, Tribulo H, Tribulo R, Mapltoft RJ, Bo GA. 

Superovulation of beef cattle with a split-dose intramuscular administration of Folltropin-V in two concentrations of hyaluronan.  Theriogenology 2012;77:1679-1685.

Vega VMB, Chavez SPJ, Franco CDM, Ramos TI, Toledo JR.  FSH in superovulation.  Revista Bionature, 2019;812-816.

Wilson JM, Jones AL, Moore K, Looney CR, Bondioli KR.  Superovulation of cattle with a recombinant-DNA bovine follicle stimulating hormone.  Animal Reproduction Science, 1993;33(1):71-82.

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