1. reproductive pharmacology

what allows dominant follicles to have an ovulatory response to the LH surge from the anterior pituitary?

granulosa cells of dominant follicles acquire LH receptors during the dominance phase

why do lactating cows have shorter durations of estrus than heifers?

high milk production → ↑ energy requirements → ↑ feed intake → ↑ liver blood flow → ↑ metabolism of E2 & P4 → ↑ clearance rate

biochemical classification of progesterone

steroid

progesterone source

corpus luteum & placenta

what are the target tissues for progesterone?

• uterine endometrium

• mammary gland

• myometrium

• hypothalamus

• anterior pituitary

progestins mechanism of action

• P4 receptor agonist

• inhibits LH secretion by inhibiting GnRH release → suppresses ovulation/estrus

• timed estrus resumes upon withdrawal

• protects against myometrial contractions (premature labor)

progestins adverse reactions

pyometra in dogs

progestins contraindications

in ruminants, reduced fertility of subsequent estrus with prolonged use without induction of a new follicular wave

biochemical classification of PGF2α

prostaglandin

PGF2α source

CL & vesicular glands of uterine endometrium

what are the target tissues of PGF2α?

• corpus luteum

• uterine myometrium

• ovulatory follicles

PGF2α mechanism of action

activates prostaglandin F2α receptor (G_q-coupled) → uterine contraction, luteolysis

PGF2α uses

• synchronization of estrus

• pyometra in cows

• induce abortion and parturition (dogs and cows)

PGF2α contraindications

• cardiopulmonary disease

  • tachycardia & asthma are possible adverse effects

• pregnancy (unless abortion is desired)

• closed pyometra in dogs → contraction can lead to rupture

dinoprost vs. cloprostenol

dinoprost

• native PGF

• metabolized & inactivated in lungs → requires high dose to ensure enough reaches ovary after going through systemic circulation

• short half life

cloprostenol

• synthetic PGF analogue

• benzyl chloride ring makes molecule more resistant to endogenous metabolism → lower dose required

• longer half life

why does the return to estrus in cows vary after being given PGF2α treatment?

• CL is unresponsive to PGF early in estrous cycle

• cows may be in different stages of follicle development at the time of PGF2α treatment

  • follicles in early stages of development take longer to grow, achieve peak [E2], and induce a GnRH surge than follicles in a later state of development

• not all cows show estrus after PGF due to anovulation or lack of detection or expression of estrus

biochemical classification of GnRH

neuropeptide

GnRH source

hypothalamic surge & tonic centers (secrete pulses)

GnRH target tissue

anterior pituitary lobe (gonadotroph cells)

GnRH mechanism of action

activates GnRH receptor to stimulate anterior pituitary surge release of LH/FSH → induce ovulation and increase gonadal steroid synthesis

GnRH clinical uses/contraindications

clinical uses

• induction of ovulation or follicular luteinization

• cystic ovaries therapy

• synchronization of ovulation protocols for timed artificial insemination or embryo transfer

contraindications

• none listed

what interaction does GnRH have with progesterone?

• GnRH-induced LH surge is significantly reduced in high circulating progesterone concentrations

• 200µg dose of GnRH increases LH surge compared to 100µg dose in high progesterone

what is the basic Ovsynch program?

• day 0: GnRH → may induce ovulation and/or luteinization of a large follicle, but more importantly, it recruits a new follicular wave

• day 7: PGF → induces luteolysis

• day 9: GnRH → causes LH surge, which induces synchronous ovulation of a dominant follicle from follicular wave recruited by initial GnRH treatment on day 0

• day 10: timed artificial insemination → ideally 16-20h after second GnRH injection (4-16h prior to ovulation)

besides synchronizing ovulation, what is the Ovsynch protocol used to treat?

currently, best option to treat ovarian cysts

biochemical classification of hCG

glycoprotein

hCG source

syncitiotrophoblast cells of the placenta (chorion)

hCG target tissue (in females)

LH receptors in the ovary

hCG mechanism of action

• strong agonist of LH receptors (mimics LH) → induces ovulation / androgen synthesis; also, weak FSH agonist

• stimulates synthesis of progesterone by the CL for finfish spawning

hCG uses

• infertility therapy in mares and stallions

• cystic ovaries in cows

why is hCG used over LH?

• LH is too rapidly metabolized

• hCG is more glycosylated than LH, which makes it more resistant to metabolism

biochemical classification of FSH

glycoprotein

FSH source

porcine pituitary-derived; contains a low amount of LH

FSH target tissue (in females)

granulosa cells

FSH mechanism / clinical use

• agonist of FSH receptors → induce estradiol synthesis & follicular development

• used to induce superovulation in beef and dairy heifers/cows

how is FSH administered?

• must be injected IM 2x daily for 4-5 days to successfully induce multiple ovulations

• biphasic elimination with t_1/2 ~5 hours

oxytocin source

neuropeptide synthesized in hypothalamus and stored in posterior pituitary

oxytocin target tissue (in females)

uterine smooth muscle cells

oxytocin mechanism

activates oxytocin receptor (G_q-coupled) on smooth muscle myocytes to increase contraction

clinical uses for oxytocin

• accelerate parturition

• evacuate postpartum debris (for vaginal birth or c-section)

• facilitate uterine involution after c-section

• metritis

• induce milk letdown

oxytocin contraindications

• dystocia caused by abnormal presentation of fetus until corrected

• only use prepartum when cervix has been relaxed

• closed pyometra