Reproductive Pharmacology

Front 1

Why might a vet wish to use drugs to alter activity of the reproductive system?

Back 1

1. Treat infertility in an animal

2. Control the time of mating or puberty

3. Control the number of progeny

4. Terminate a pregnancy or pseudopregnancy

5. Induce or delay parturition

6. Influence behavior

Front 2

Hormones which may be manipulated and used in reproductive pharmacology?

Back 2

1. Gonadotrophin Releasing Hormone (GnRH)

2. Gonadotrophins (LH & FSH)

3. Melatonin

4. Steroid hormones (estrogens, androgens, progesterones)

5. Prostaglandins

5. Oxytocin

Front 3

Synthetic GnRH licensed in vet med?

Back 3

1. GONADORELIN

2. BUSERELIN (20x more potent then GnRH)

3. DESLORELIN (144x more potent)

Front 4

GnRH can stimulate and inhibit gonadotrophin secretion.

True or False?

Back 4

TRUE - pulse frequency is key!

- Infrequent GnRH pulses = stimulatory

- Frequent/constant GnRH pulses = inhibitory (flare effect = initial response, but then fades out)

Front 5

Changing the 6th and 10th ___________ peptides in GnRH result in a drastic ____________ in potency in the analogues created. List two GnRH analogues which experience this.

Back 5

Changing the 6th and 10th GLYCINE peptides in GnRH result in drastic INCREASES in potency in the analogues created.

- BUSERELIN = 20x more potent

- DESLORELIN = 144x more potent

Front 6

What are the three methods of using GnRH in vet med? Give an example of use for each method.

Back 6

1. Single Injection (IM) - e.g. gonadorelin

- Used for diagnostic testing for reproductive disfunction, promoting ovulation, inc conception rates, stopping follicular cysts (cattle and bitches) & stripping eggs in fish

2. Continuous (subcut implant)

- Used for contraception, induction of abortion, behavior management, stopping hormone-dependent tumor growth, postponing puberty

3. Pulsatile (using pumps)

- Used for induction of reproductive function

Front 7

Adverse effects of using GnRH analogues in vet med?

Back 7

FEW

- Failure to recover reproductive function

- Hypo-estrogenism

Front 8

Describe the process of treating cystic ovary disease in a dairy cow.

Back 8

Upon diagnosis of a follicular cyst (palpation):

1. Dose with 5ml of GnRH analogue (Gonadorelin)

= stimulates ovulation of follicle and growth of CL

2. 7-9 days later dose with 2ml prostaglandin F2alpha analogue (Estrumate)

= regression of CL and heat follows 3-5 days later

Front 9

Deslorelin implants (GnRH agonist analogues) used in dogs to _________________________.

Back 9

INHIBIT REPRODUCTION (last 6-12 months, depending on size)

Front 10

GnRH antagonists are being developed for what types of treatment?

Back 10

1. Contraceptive

2. Abortifacient

3. Control of some steroid dependent cancers

Front 11

GnRH antagonist advantages? Disadvantages?

Back 11

ADVANTAGES:

1. Immediate

2. Reversible

3. Longer Half-lives (hours)

4. No flare effect

DISADVANTAGES:

1. Histamine reactions

2. Lowers gonadal steroid concentrations

Front 12

Gonadotrophins used in vet med? Sources?

Back 12

1. LH - ant pituitary

2. FSH - ant pit; extracts from ovine (oFSH) and porcine (pFSH)

3. Chorionic gonadotrophins = human corionicgonadotrophins (hCG) = LH effects

4. Serum gonadotrophins = pregnant mare syndrome gonadotrophin (PMSG) = FSH effects

Front 13

Use of GONADOTROPHINS in vet med repro pharm?

Back 13

1. SUPEROVULATION, prior to embryo transfer

2. ADVANCEMENT/SYNCHRONIZATION OF REPRO BEHAVIOR

3. INDUCTION OF OVULATION

4. ENHANCE/TEST MALE FERTILITY

- e.g. hCH increases libido & spermatogenesis

5. DIAGNOSE CRYPTORCHIDISM (or incomplete gonadectomy) & treat

Front 14

Describe the potential protocol for the use of gonadotrophins for superovulation.

Back 14

Day 0: Progesterone used intravaginally for up to 8 days, which provides negative feedback on the hypothalamus GnRH release temporarily.

Day 8 = Progesterone is removed and oFSH is given to stimulate rapid growth of follicles, resulting in a rise

Day 13 = LH Surge & ovulation

* AI performed after ovulation and embryos collected soon after to be transplanted into other cows.

Front 15

Describe how gonadotrophins are used in vet med to detect cryptorchidism (or incomplete gonad removal).

Back 15

Mainly used in horses & dogs!

- hCG given (usually administered as single IM or IV injection

- If rise in T follows after hCG injection = CRYPTORCHID

- In no T = No testes!

Front 16

________________ may be used to manipulate time of breeding in certain animals, particularly in sheep.

Back 16

MELATONIN

Front 17

Describe the use of melatonin for manipulating breeding season in sheep.

Back 17

Increasing melatonin tricks the sheep pineal gland into thinking the days are shorter (melatonin produced at night normally)

- Melatonin implant given about 40 days prior (lag period) to the time at which the farmer wishes to breed.

- Typically this about mid april, so that breeding occurs in early June.

* Melatonin also results in an increase in progeny.

Front 18

Melatonin use in sheep commonly results in an increase in progeny.

True or False?

Back 18

TRUE

Front 19

Steroids have actions on many tissue and processes including:

Back 19

1. Reproductive axis

2. Uterus

3. Mammary glands

4. Bone formation

5. Lipoprotein Metabolism

6. Inflammation

7. CNS

8. Growth

Front 20

List the vet licensed steroidal estrogens:

Back 20

1. Oestradiol benzoate (Mesalin)

2. Estriol (Incurin)

Front 21

Pharmacokinetics of Estrogens used in reproductive vet med?

Back 21

- Rapid hepatic metabolism and urinary excretion

- Esters prolong half-life

- Ethinyl group increases oral bioavailability

- Rapidly absorbed from mucous membranes, GIT

- Bound to plasma proteins - sex-hormone binding globulin (SHBG)

- Concentrations occur in plasma and milk following administration so be aware when giving to soon to be moms

Front 22

Uses of estrogens in vet practice?

Back 22

1. Synchronization/induction of estrus and ovulation

2. Misalliance (termination of pregnancy), but not used commonly for this anymore... not very accurate and practical; other methods use for this now...

3. Urinary incontinence after spaying (e.g. estriol)

4. Chronic endometritis (cows = low dose)

5. Anal adenomas, prostatic hyperplasia, libido (dog)

Front 23

Estrogens not used as much anymore due to the amount of side effects.

True or False?

Back 23

TRUE - Particularly due to the aplastic anemia effects in dogs and cats!

Front 24

Side effects of estrogens in vet practice?

Back 24

1. Aplastic anemia (dogs & cats)

2. Thromboembolism

3. Cystic endometrial hyperplasia (bitches)

4. Cystic ovaries (cattle & pigs)

5. Carcinogenic!

6. Squamous metaplasia of prostate

7. Abortion and congenital defects!

8. Acute uterine infection

Front 25

Clinical uses for androgens (testosterone) in vet med? Give licensed drug for vet med.

Back 25

USED FOR:

- Deficient libido

- Hormonal alopecias

- Reversal of feminization (sertoli cell tumors)

- Suppression of estrus in bitch (racing greyhounds)

LICENSED: DURATESTON

Front 26

Side effects of androgen use in vet med?

Back 26

- Aggression

- Impaired growth in young (closed growth plates)

- Congenital defects

- Edema

Front 27

Uses of anti-androgens in vet med?

Back 27

USED MORE THAN ANDROGENS IN VET MED!

- Prostate hypertrophy or carcinoma

- Hypersexuality

- Behavioral problems

Drugs: Flutamide, finasteride

Front 28

Progestogens are widely used in vet med.

True or False?

Back 28

TRUE

Front 29

In which animals is progesterone ONLY PRODUCED BY THE CORPUS LUTEUM?

Back 29

Dog

Pig

Goat

Rabbit

Front 30

Clinical uses of progesterone in vet med?

Back 30

1. Synchronize/induce estrus and ovulation

2. Prevention/suppression of estrus and ovulation

3. Treatment of cystic ovaries

4. Pseudopregnancy

5. Estrogen & androgen dependent tumors

6. Aggression and behavioral problems

7. Miliary eczema, eosinophilic granulomas (cats)

8. Prevention of abortion (cats and dogs)

Front 31

Pharmacokinetics of progesterones?

Back 31

- Rapid hepatic metabolism and urinary excretion (Half-life = ~5 min)

- Slow metabolism induced with substitutions of A ring (e.g. Medroxyprogesterone acetate (MPA) and megestrol acetate (MA))

- Orally active with ethinyl group

- Spp differences in potency and efficacy

Front 32

Examples of licensed progestagens used in vet med? Species licensed for?

Back 32

1. Medroxyprogesterone acetate (MPA) = injection in dogs and cats

2. Megestrol acetate (MA) = oral, dogs and cats

3. Delmadinone acetate = SC or IM, dogs and cats = prostate hypertrophy treatment

4. Flugestone acetate = Intravaginal, sheep & goats

5. Altrenogest = oral, horses & pigs

6. Progesterone = Intravaginal, cattle & sheep = used for synchronizing breeding!

Front 33

Adverse effects of progesterones?

Back 33

Increases proliferation and secretory activity of the endometrium and so can result in the following:

- Cystic endometrial hyperplasia

- Pyometra

- Mammary hypertrophy

- Weight gain

- Diabetes mellitus

Front 34

Contraindications of progesterones?

Back 34

Paricular to small animals:

- Diabetes mellitus

- Liver disease

- Mammary tumors

Front 35

Progesterone receptor ANTAGONISTS? Use?

Back 35

ALIZINE & AGLEPRISTONE

USE:

Misalliance = termination of pregnancy in the bitch

- Blocks the progesterone receptor itself, so dog still is normally producing the hormone, but it's not being detected so pregnancy isn't maintained.

- Can actually detect that the animal is pregnancy before giving drug by detecting "relaxin" levels = pregnant

= better option then using estrogen!

Front 36

Describe the process of inducing misalliance in a bitch using a progesterone receptor antagonist.

Back 36

ALIZINE or AGLEPRISTONE

Two SC injections given 24 hours apart

- Up to 45 days after mating (so can actually test for pregnancy before going through with treatment, unlike with estrogen treatment)

Downside = painful :(

Front 37

Uses of prostaglandin in vet med?

Back 37

1. Synchronization of estrus

2. Prolonged diestrus in the mare

3. Treating luteal cysts in cows

4. Pyometra (open)

5. Termination of pregnancy (although progesterone receptor antagonists are better for dogs)

- Cows = before 150 days

- Sheep = before 50 days

- Mares = before edometrial cups/~35 days

6. Induction of parturition in cows and pigs

7. Ceases pseudopregnancy in goats

Front 38

Pharmacokinetics of PROSTAGLANDINS?

Back 38

1. VERY RAPID METABOLISM

2. Compounds:

- Synthetic = Dinoprost

- Analogues = Cloprostenol, luprostiol

3. Administration:

- Single IM injection

Front 39

Side effects of prostaglandins?

Back 39

1. Smooth muscle constriction: Bronchospasm!

2. Sweating, colic, vomiting

3. Tachycardia (inc HR)

4. Vasoconstriction

5. Miscarriage

Front 40

Name a licensed dopamine receptor agonist in vet med and give uses.

Back 40

CABERGOLINE (POM-V)

Dopamine induces negative feedback on lactotroph receptors in the ant pit which release prolactin; so dopamine agonists result in reduced prolactin release...

Uses:

- Terminate pregnancy (bitch)

- Terminate pseudopregnancy

- Suppress lactation

Front 41

Name a licensed oxytocin drug in vet med. Uses of oxytocin in vet med?

Back 41

CARBETOCIN = UTERINE STIMULANT

Uses:

- Dystocia (w/ no physical obstruction)

- Post-partum hemorrhages reduced

- Removal of retained placenta

- Pyometra (open)

- Induction of parturition

- Initiation of milk ejection

Front 42

Name two veterinary licensed myometrial relaxants. Uses?

Back 42

Clenbuterol & Vetrabutine = B2 adrenoreceptor agonists = relax smooth muscle and coordinate contractions

USES:

- Delay of parturition

- Facilitate uterine manipulation

- Ringwomb in sheep