Reproductive pharmacology Flashcards
GnRH actions
Stimulatory action: released relatively infrequently, i.e. once per hour. Each episode of GnRH release stimulates LH release. Pulsatility is key. GnRH released in protal vessels, otherwises it gets chewed up too quickly in systemic circulation.
Synthetic GnRH: fertirelin, Gonadorelin
GnRH can also inhibit gondatrophin secretion. If GnRH is given/secreted too frequently, as infusion or implant, will get inhibitory action after a while. Initial flare effect is stimulatory. Eventually LH secretion is dampened and inhibits rest of reproductive axis.
Structure of GnRH and relative potentcy of analogues
analogs: substitute position 6 (glycine) and 10 (glycine)
Buserelin: D-serine at 6, N-Et at 10–20x more potent than GnRH
Deslorelin: D-Trp at 6, N-Et at 10–144x more potent than GnRH
Increased potentcy and also increased half life than GnRH
nb: GnRH half life is around 4 minutes
Uses for GnRH in vet practice
Drugs: burserelin (analog), Gonadorelin (synthetic GnRH), deslorelin (analog)
Single injection (positive stimulatory effect): IM–1) diagnostic test for whether reproductive axis is working; 2)promote ovulation; 3) increase conception rates; 4) follicular cysts in cattle and bitch; 5) stripping eggs in fish
Continous: (subcutaneous implant)– 1) contraception 2) induction of abortion 3) behaviour management (inhibit T-secretion) 4) hormone dependent tumours 5)postponement of puberty- i.e. animals not growing well
Pulsatile: (using pumps) for induction of reproductive function
Withdrawal periods: nil
Adverse reactions: very few, but failure to recover repro function; hypo-estrogenism
Benefit of using GnRH: small molecule, doesn’t stimulate immune response (cf. FSH and LH)
Single injection of GnRH: promotion of ovulation and diagnostic test for repro function
Gonadorelin: promote ovulation
Diagnostic test for repro function: If pituitary problem, if you give GnRH, LH, Testosterone or estrogen will not increase. If gonadal problem, LH will increase, but testosterone/estrogen will not increase. (i.e. LH not translated into androgen increase).
Single injection of GnRH: COD
Treatment of cystic ovary disease in cattle (COD): cattle in post-partum period; 30-60 days after calving; 5-30% of animals that don’t come back in season. Increases calving interval by 22-65 days
Reason: persistence of dominate follicle which hasn’t ovulated and is producing high estrogen– arrests next cycle and causes behavioral problems.
No CL, low progesterone levels. Progesterone causes formation of LH receptors on dominant follicle. If there are few LH receptors, it doesn’t respond appropriately to LH. Natural levels of LH aren’t high enough to elicit a response.
Treatment: Diagnosis of follicular cyst via rectal palpation. GnRH injection ruptures dominant follicle. CL forms for 7-9 days. Then give PGF2alpha (estrumate) injection. After 3-5 days, cow goes into oestrus.
Use of a GnRH agonist to inhibit reproduction: continuous implant or infusion
Deslorelin implant: Supralorin 6 or Supralorin 12–fertility control
Pros: temporary (can be removed), no surgery required, safe (no scarring), alters undesirable behavior, rapid mass sterilization, facilitate healthy monitoring. Also, can treat benign prostatic hyperplasia (stimulated by androgens)
Can also use for tx for urinary incontinence.
nb: get initial flare-up of stimulation of repro axis
Future: GnRH antagonists
used in human medicine, used to lower steroid levels in certain cancers.
Uses: contraceptive, abortifacient, control of some steroid dependent cancers
Advtanges: immediate, reversible, longer half lives (hours), no flare effect (because it’s blocking the receptor)
Disadvtanges: histamine reactions (older products), lowering of gonadal steroid concentrations.
Use of gonadotrophins in veterinary practice (i.e. FSH and LH)
Leutinizing hormone: LH from anterior pituitary gland
Follicle stimulating hormone: FSH from anterior pituitary gland (extracts of pituitary gland: oLH, oFSH, pFSH)
Chorionic gonadotrophin: hCG- predisposition to act through LH. complex glycoprotein from urine of pregnant women
Serum gonadotrophin (eCG/PMSG): complex glycoprotein from mare’s serum- predominantly FSH effects
Chemistry:
Glycoproteins: alpha (common to LH and FSH) and B subunits- Beta are hormone and species specific)
Chorulon (hCG)
PG 600 (hCG and PMSG)
PMSG
Examples of use of gonadotrophins
A) superovulation
b) advancement and synchronization of reproductive behaviour
c) induction of ovulation
d) enhance or test male fertility
e) diagnose cryptorchidism (or incomplete gonadectomy) and treat (in specific cases)
Superovulation using gonadotrophins
Superovulation prior to embryo transfer in order to produce a lot of good embryos
FSH/PMSG stimulate primordial follicles to become antral and eventually dominant follicles–>fertilize–>embryo transfer
Potential protocol: Progesterone vaginal impant to inhibit reproductive axis–>dominant follicles can’t ovulate). After 8 days, start giving injections (oFSH need to give a lot of injections, if giving PMSG, fewer injections)–> remove progesterone implant around day 10 or 11. LH surge at day 13, AI around day 14 and collect embryos around day 19.
Advancing estrous and synchronizing ovulation using gonadotrophins
FSH/PMSG given for:
Bitch: anestrus 5 days, hCG for surge
Sheep and goats: advance time of follicular growth and ovulation–synchronize with progestagens
Cattle: acylic
Give FSH/PMSG at end of luteal phase (i.e. when progesterone is decreasing).
Perhaps also give LH injection to promote ovulation
Inducing ovulation using gonadotrophins
hCG given as a boost to endogenous LH
Enhancing/testing male fertility using gonadotrophins
hCG stimulates production of testosterone from leydig cells (remember hCG acts through LH). hCG–>interstitial cells–>increase T–>increase libido and increase spermatogenesis in seminiferous tubules.
Decting cryptorchidism/incomplete gonadal removal using gonadotrophins
nb: cryptorchid testes more likely to get sertoli cell tumours; also, cryptorchid testes still produce testosterone which can cause behavioral problems.
Measure T in serum. Give hCG, if there are no testes, there will be no increase in testosterone. If animal is cryptorchid, can measure increase in serum testosterone.
Administer as a single IM or IV injection
Mainly in horses and dogs
Ethical issues: inherited condition- in dog autosomal recessive gene
nb: can have temporary inguinal crytporchidism but could go on to breed. Testosterone can help testicular descent if testes are held quite low.
Melatonin
melatonin is secreted in circadian rhythym. Melatonin is only released at night, therefore melatonin is low during the day and increased at night.
Sheep are short-day breeders, therefore can use melatonin to alter breeding in sheep. Melatonin acts on G-coupled receptor in the brain.
Melatonin secreted from pineal gland of sheep (at back of 3rd ventricle)
Use of melatonin to time the breeding season
Melatonin (e..g regulin) as an implant.
Introduce regulin in april- high melatonin animal sees it as an ultra-short day–> gear up repro system. Breeding season can then start in June, rather than september.
takes about 40 days for melatonin to act
Ram effect: when you introduce strange ram and measure LH, ram goes in and through olfactory system–> increase LH pulse frequency–>ovulation.
nb: melatonin can also cause an increase in progeny: synchronize and cause a couple of DFs to ovulate–> greater incidence of twins.
Steroid hormones: estrogens, progesterones, androgens
steroids have actions on many tissues and processes including: repro axis, uterus, mammary tissue, bone formation (tend to close epiphysis), lipoprotein metabolism, inflammation, CNS, growth
Oestrogenic compounds
repro steroids are all formed from cholesterol
Steroidal oestrogens:
oestradiol and esters (better pharmacokinetics and longer half life)
Oestradiol benzoate(EB) (Mesalin)- given IM or SC- formulated in oil
Oestradial valerate (EV)
Oestradiol cypionate (EC)
Ethinylestradiol (oral bioavailability)
Estriol (Incurin)- natural estrogen used for incontinence in spayed bitches
Receptors for estrogens: ER alpha and ER beta- nuclear hormone receptors where they affect transcription of various genes.
Pharmacology of Estrogens
EB,EV,EC: synthetic esters, absorbed and hydrolyzed in the body
All steroid hormones undergo rapid hepatic metabolism and urinary excretion (as sulphates or glucoronides)
Esters prolong half-life (EB/EV) to combat rapid metabolism and excretion
Ethinyl group: increases oral bioavailability
Rapidly absorbed from mucous membranes/GIT
Injections in oil or implants increase persistence (prolongs half life because they’re released slowly from oil)
Bound to plasma proteins (sex hormone binding globulin- amount of this protein can change i.e. insulin decreases amt of SHBG–> more steroid is free and able to act) and ethinylestrodiol is bound to albumin.
After administration (cows) of 17betaE, EB, EV, concentrations in plasma and milk are within physiological range.
Uses of oestrogens in veterinary practice
Synchronization/induction of estrus and ovulation (also can do GnRH or LH)
Misalliance (EB): potential toxic effects- not strongly recommended for use for abortion because it’s negative effects. E stops transport of zygote down fallopian tube (need to give VERY early on);also makes uterus hostile environment for implantation. NB: can’t tell if bitch is pregnant for 28 days (measure relaxin)– may be aborting a pregnancy that’s not even there.
Urinary incontinent after spaying (estriol)
Chronic endometriosis (cow: low dose)- if used for acute, very bad news. Estrogens tend to absorb toxins. If you have a gram negative bacteria causing the endometriosis, releases toxins, E allows absorption of those toxins.
Anal adenomas, prostatic hyperplasia, libido (dog): Ethinylestradiol (under the cascade)- negative feedback actions–> lowers FSH, LH and androgens.
Side effects of estrogens
thromboembolism
*Aplastic anemia (can be life threatening)- cats and dogs
Cystic endometrial hyperplasia (bitches)
Cystic ovaries (cattle and pigs)
Carcinogenic (e.g. diethylstilbestrol: prohibited in food producing animals)
Squamous metaplasia of prostate (dogs)
In pregnancy: abortion, congenital defects
in acute uterine infection, increase absorption of toxins
Androgens: indications
Deficient libido
hormonal alopecias- certain androgens also can act on glucocorticoid receptors
reversal of feminisation (sertoli cell tumours)
Suppression of estrus in bitch (racing greyhounds)
Examples of androgens used in vet med: methyltestosterone e.g. Orandrone; mixed esters e.g. Durateston- long duration of activity
Side effects: aggression, impaired growth in young (by closing epiphyses), congenital defects, oedema (so not in animals with impaired kidneys/liver), virilisation in females
Anti-androgens
in order to reduce potent androgens without effecting testosterone function–> no feminisation
Flutamide: non-steroidal androgen receptor antagonist- blocks effects of endogenous androgens
Finasteride: enzyme inhibitor; blocks 5 alpha reductase (T –> dihydro T (which is much more potent than testosterone).
uses: prostate hypertrophy or carcinoma
hyper sexuality
behavioral problems
Progestagens-indications
synchronize/induce estrus and ovulation
prevention or suppression of estrus and ovulation
treatment of cystic ovaries
pseudopregnancy
oestrogen/androgen dependent tumours- using negative feedback
Aggression/behavioural problems
Miliary eczema (can act through glucorticoid receptors), eosinophilic granuloma (cats)
Prevention of abortion (cats and dogs): particularly those which don’t have sufficient progesterone through CL
Pharmacology of progestagens
Rapid hepatic metabolism and urinary excretion- half life around 5 minutes
usually formulated as some kind of ester
slow metabolism with substitutions to A ring
Orally active with ethinyl group
Species differences in potency and efficacy
Examples of progestagens in vet med
Medroxyprogesteron acetate: by injection, dogs and cats
Megestrol acetate: oral, dogs and cats
Proligestone: IM, dogs, cats, ferrets
Delmadinone acetate: SC or IM, dogs and cats
Flugestone acetate: intravaginal, sheep/goats
Altrenogest: oral, horses, pigs
Progesterone: intravaginal, cattle, sheep (CIDR) controlled internal drug release. INhibits repro axis and when it’s removed–> synchronization.
Adverse effects of progesterones
cystic endometrial hyperplasia
pyometra
mammary hypertrophy
weight gain
diabetes mellitus
Contraindications (small animals): diabetes mellitus, liver disease, mammary tumours
Progesterone receptor antagonists
Blocks receptor for progesterone.
Mifepriston (RU 486)- no vet license– morning after pill
Aglepristone (RU 534)- licensed for misalliance in bitch
Alizine
Misalliance: 2 injections, subcutaneous 24h apart, up to 45 days after mating.
P high for 60d in pseudopregnant animals as well as if pregnant.
Prostaglandins
PGF2alpha causes regression of the CL (after refractory period)–> decrease in progesterone
PGF2alpha goes to ovary via special counter-current exchange–> causes regression of CL 1) animal will return to cycling or 2) if animal is pregnant, will lose pregnancy
Refractory period in cow, mare, ewe and dose is 5 days after ovulation. If you give before 5 days, no PGF2alpha receptors, no effect.
Pig refractory period=11 days
Bitch is unresponsive to PGF2alpha- need to give multiple injections- support for CL in bitch is due to trophic hormone (LH or Prl).
Prostaglandins in vet practice- indications
synchronization of oestrus
prolonged disestrus in mare
luteal cysts in cow
pyometra (open)- if closed, can cause rupture- PGF2 alpha will cause contraction of uterus and expel contents.
Termination of pregnancy: Cows- before 150 days, sheep before 50 days, mares before endometrial cups (day 35), bitch after day 30 (repeated doses, not a good idea).
Induction of parturition in cows and pigs (incl. mummified fetus)- towards v. end of pregnancy i.e. overterm or dead fetus
Pseudopregnancy in goats
Pharmacology of prostaglandins
very rapid metabolism- synthetics have a longer half life
compounds: synthetic: dinoprost; analogues (closprostenol, luprostiol)
Administration: single IM injection- be very careful as administer because it can cause bronchospasms and contractions of other muscles- can cause abortion in women
Side effects: smooth muscle constriction (bronchospasm); sweating/colic/vomiting/tachycardia; vasconstriction; severe cellulitis at injection site; miscarriage.
Dopamine receptor agonists
Serotonin inhibits dopamine secretion. Dopamine inhibits Prl.
Prl responsible for: mammary development, milk production, support of canine and feline CL.
Dopamine receptor agonists: Bromocriptine (under cascade) –> terminate pregnancy of bitch (can get into brain and cause nausea/vomiting)
Cabergoline–> terminate pseudopregnancy
Metergoline (anti-serotonin action)–>suppress lactation.
CL in bitch supported by LH and Prl. Release of Prl is stimulated by TRH and inhibited by dopamine. D receptor will suppress Prl release and will withdraw support for canine/feline CL.
Oxytocin
uterus contractions and milk let down
Myometrial stimulants: oxytocin
Nonapeptide, stored in posterior pituitary; ferguson reflex; estrogen induced receptors.
Metabolism is very rapid; half life is 1-5 minutes (alter NH2 or position 8)
Compounds: extracts of posterior pituitary (also contain vasopressin ADH); synthetic (non-contaminated)
Admin: IM or IV (S.c. may cause abscess)
Pulsatile vs. low-dose continuous
Examples: oxytocin S, carbetocin (much more active, less quickly metabolised).
Indications of uterine stimulants: parturition
dystocia: no physical obstruction
postpartum hemorrhage: contractions clamp down on bleeding vessels
removal of retained placenta
uterine infection (open)
induce parturition- after a certain point in time
Initiation of milk ejection
OT needs OT receptors. only present in uterus at v. end of pregnancy (won’t cause abortion in mid-pregnancy). Estrogen causes OT receptor formation in myometrium and endometrium and mammary tissue. Estrogen rises at the end of pregnancy.
Myometrial relaxants
Delay parturition
facilitate uterine manipulation
ringwomb in sheep
B2 adrenoceptor agonists: relax smoothe muscle and coordinate contractions
clenbuterol, vetrabutine
nb: handling and sotrage because they can cause contractions.
Contraceptive methods in wild populations
contraceptive vaccines: GnRH vaccine, porcine zona pellucida vaccine
bird fertility control: nicarbazin, diazacon
