1. Art and Diseño

Histrelin and its use in Mares
Patrick J. Burns, Ph.D. & Richard M. Gilley B.S.
BioRelease Technologies Lexington, KY (www.BioReleasetechnologies.com)
Gonadotropin releasing hormone (GnRH) is a naturally occurring decapeptide in mammals, including
humans. The biologic action of GnRH (LHRH) is to stimulate the pituitary to release gonadotropins,
especially luteinizing hormone (LH), but, also, follicle stimulating hormone (FSH). LH, in concert with
FSH, stimulates ovarian follicular development; the LH surge ovulates the follicle. The most sensitive
assay for exogenously administered GnRH is the detection of serum changes in LH concentration
following GnRH administration. The plasma half-life elimination phase of GnRH in humans has been
reported to be 13-27 minutes using radioimmunoassys specific for GnRH. Some analogues of GnRH
such as deslorelin and histrelin with substitutions in the 6 and 10 positions have increased and prolonged
biological activity due to increased structural and metabolic stability. Histrelin is one such analog which
differs from natural GnRH in position 6 where Glycine (GLY) has been replaced with Histidine (Bzl)
and in position 10 where glycinamide has been replaced by N-ethylamide as illustrated below.
GnRH: pPGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2
Histrelin: pPGlu-His-Trp-Ser-Tyr-His(Bzl)-Leu-Arg-Pro-NHEt
In man, the plasma half-life of histrelin was about 8 times that of native GnRH and about double that of
deslorelin which is partially responsible for its enhanced potency as illustrated below.
Comparative Potency Ranking to GnRH*
Potency Estimate to GnRH
Dose relative to DA
Leuprolide
15
Buserelin
20
Deslorelin
144
1.5 mg
Histrelin
210
1.0mg
*Ascoli M, Segaloff DL. Adenohypophyseal Hormones and their Hypothalamic releasing factors.
In Hardman JG, Limbird LE, Molinoff PB, Ruddon RW, Gilman AG, eds, Goodman & Gilman’s
The Pharmacological Basis of Therapeutics, 9th ed. New York, New York : McGraw Hill 1996
1363-1382
BioRelease Histrelin Clinical Results
Because of Histrelin’s enhanced pharmacodynamic properties, BioRelease Technologies has initiated
preliminary laboratory studies on a specially formulated BioRelease Histrelin. Results from initial
studies suggested that both doses (0.5 mg and 1 mg) of BioRelease Histrelin resulted in ovulation in >
95% of estrus mares treated after follicle size and uterine edema scores met normal farm treatment
parameters.1 Because this study (STUDY 1) was conducted after May, additional studies early in the
breeding season are also being reported (STUDY 2 & 3).
Study 1 – Table 1
Comparison of Deslorelin and BioRelease Histrelin for Induction of Ovulation in Mares 1
Interval to Ovulation
Ovulation within 48 h
Treatment
Dose
(n)
(days)
(% of mares)
Deslorelin*
1.5 mg
30
1.97 ± 0.5b
93% b
BioRelease Histrelin**
1.0 mg
19
1.63 ± 0.6 b
95%b
b
Biorelease Histrelin **
0.5 mg
18
1.83 ± 0.4
100%b
* Francks Pharmacy, Ocala, FL
** BioRelease Technologies Lexington, KY USA (Shipped and stored at room temperature)
STUDY 2 - Previous studies in our laboratory have suggested that doses of BioRelease Histrelin induce
ovulation in >95% of mares after May 1st. The present experiment was designed to compare the effectiveness of
a single 1mL injection containing 0.25 mg, 0.5 mg or 1.0 mg of Histrelin for inducing ovulation in cyclic
recipient mares prior to April 6th in northwestern Texas.
Cyclic recipient mares were chosen from the herd based on 1) the previous detection of ovulation or a functional
CL by US exam. Ovulatory induction treatments (Blinded BioRelease Histrelin: BLUE, GREEN OR RED) were
used by the investigator after follicle size and uterine edema scores meet normal farm treatment parameters.
Following treatment, mares were evaluated until ovulation. Percentage of mares ovulating within 48 hours are
presented below.
Study 2 - Table 2
Evaluation of BioRelease Histrelin for inducing ovulation
in cyclic mares early in the year : Effect of Dose2
Ovulation within 48 h
Treatment
Dose
(n)
(% of mares)
BioRelease Histrelin*
0.25 mg
19
84.2%a
BioRelease Histrelin*
0.5 mg
19
89.5%a
BioRelease Histrelin*
1.0 mg
20
85.0%a
All Doses
58
86.2%
* BioRelease Technologies Lexington, KY USA (Shipped and stored at room temperature)
Results from Study 2 confirmed that all three doses of BioRelease Histrelin were equally effective at inducing
ovulation early in the year 2 (Feb 25 – April 6th).
STUDY 3 - The goal of this study was to compare the efficacy of two dose rates of Histrelin (0.5 and 1.0 mg
given IM, Groups 2 and 3, respectively) with hCG (2,500 IU given IV, Group 1) throughout the breeding season
in one herd of pastured mares (n=88) under ambient light conditions in southeastern Texas3.
There was a non-significant trend for higher ovulation responses with both dose rates of Histrelin compared with
hCG treatment (ovulation responses within 2 days of treatment among treatment groups (31/37, 84%; 34/37,
92%; and 33/36, 92% for groups 1-3, respectively). The ovulation rates within 2 days obtained with Histrelin
were similar to those obtained in the same herd during the 2010 breeding season when 1.5 mg BioRelease
deslorelin was administered (113/128, 88%).
Study 3 – Table 3
Comparison of Efficacy of Two Dose Rates of Histrelin to Human Chorionic Gonadotropin for Inducing
Ovulation in Broodmares3
Ovulation within 48 h
Treatment
Dose
(n)
(% of mares)
hCG
2500 IU
37
84%a
BioRelease Histrelin*
0.5 mg
37
92%a
BioRelease Histrelin *
1.0 mg
36
92%a
BioRelease Deslorelin**
1.5 mg
128
88%
*BioRelease Technologies Lexington, KY USA (Shipped and stored at room temperature)
**Obtained in the same herd during the 2010 breeding season when 1.5-mg BioRelease deslorelin was
administered (113/128, 88%).
Response rates (ovulation in 2 days) appeared to be similar for both doses of Histrelin, so response rates in each
month to both dose rates of Histrelin were compared with those achieved with hCG treatment. Ovulations within
2 days of treatment were 89%, 90%, 96%, and 100% for Histrelin, compared with 75%, 83%, 89%, and 100%
for hCG, during the months of February, March, April, and May, respectively (Table 4). Although ovulatory
response appeared to improve for both products as the season progressed, no differences were detected between
response rates to Histrelin or hCG for any month .
Study 3 - Table 4
Comparison of Efficacy of Two Dose Rates of Histrelin to
Human Chorionic Gonadotropin for Inducing Ovulation in Broodmares: By Month3
Ovulation within 48 h
Treatment
Dose
(% of mares)
FEB
a
MAR
a
APR
a
hCG
2500 IU
75 ( n=8)
83 (n=18)
89 (n=9)
BioRelease Histrelin
0.5* mg & 1 mg*
89a (n=18)
90a (n=29)
96a (n=22)
*BioRelease Technologies Lexington, KY USA (Shipped and stored at room temperature)
MAY
100a (n=2)
100a (n=4)
Because eight stallions and different methods of breeding were used, no attempt was made to evaluate effects of
treatment on fertility (pregnancy rate). However, pregnancy rates per cycle were > 60% and similar to those
obtained in previous years at this farm.
REFERENCES
1. Lindholm, AGR., Ferris, RA., D.B. Scofield, DB., McCue, PM (2011)
Comparison of deslorelin and histrelin for induction of ovulation in mares.
2011 ESS SYMPOSIUM Abstracts / Journal of Equine Veterinary Science 31 (2011) p 312.
2. Blodgett, Glen (2011) Evaluation of BioRelease Histrelin for inducing ovulation
in cyclic mares early in the year : Effect of Dose. Field Study Results 2011.
3. Justin L. Voge DVM, MS, Diplomate ACT, A. Kendrick Sudderth DVM, Steven P. Brinsko DVM, MS, PhD,
Diplomate ACT, Patrick J. Burns PhD, Terry L. Blanchard DVM, MS, Diplomate ACT ( 2012) Comparison of
Efficacy of Two Dose Rates of Histrelin to Human Chorionic Gonadotropin for Inducing Ovulation in
Broodmares. Journal of Equine Veterinary Science ( available at www.j-evs.com, see articles in press).