Principles of Cycle Manipulation

Question 1

• Cluck was ‘rescued’ at the weekend. She is in poor condition and the new owner has been advised to stop her from laying eggs to allow her to divert more energy into fat reserves and to improve her general health
• What is your approach?

Answer 1

–Could try supplementing the chicken

–Manipulate the laying – don’t provide additional lighting

–Change the environment to get them to good health

–Give a GnRH agonist

Question 2

What is the ovulation positive feedback mechanism in birds?

Answer 2

Endocrine control

Top part Is the same – HT and PG

If you could block GnRH – stop stimulation of the cascade beneath that. We have GnRH agonists – given for a long period of time; stimulate to start with and then attaches to receptor and causes a down stimulation. Takes 4-5days for this

It is a depot GnRH agonist – block everything downstream

GnRH agonist is used in other species to simulate cyclicty!

Question 3

What species have anoestrus and a transitional phase to their cycle? (3)

Answer 3

–Mare – doesn’t cycle over winter (anoestrus). Once in natural breeding seasons – polyoestrus!

–Sheep – anoestrus in summer

Cats – don’t cycle over winter

Question 4

What does the average cycle look like, what hormones are there and where do they act?

Answer 4

HT – key control but there is the seasonal component from melatonin
Some species melatonin stimulate some is antagonists
HT – GnRH – PG – FSH – follicle – oestrogen (behaviour, swelling genitals, pheromones, pro oestrus and oestrus behaviour). LH is responsible for some follicle growth – mostly ovulation – CL – progesterone (prepare for pregnancy (increase mammary gland, close cervix, secretions)
Oestrogen and progesterone – (sex steroids) – responsible for negative feedback
Lots of progesterone – reduced HT and PG stimulation to prevent an excess
Polyoestrus – roughly 17 day luteal phase= due to prostaglandin lysing the CL. Reducing progesterone and reducing negative feedback
Some species (dog) – prolactin is there to support CL

Question 5

What drugs do we have acting on the hormones of the cycles?

(this is a complicated pic sorry)

Answer 5

Question 6

What is the effect of melatonin?

Answer 6

•Endogenous production in response to decreasing daylight

–Up-regulation of short-day breeders

–Down-regulation of long-day breeders

Question 7

How can we use melatonin in the ewe and mare?

Answer 7

•Ewe

–Melatonin implant administered at base of ear in May-June to hasten onset of cyclicity (+ introduction of the ram)

•Mare

–Would need melatonin antagonist (not available) to stimulate oestrus in the mare

–Daylight is effective if day-length is extended from December onwards

Question 8

What are the affects of GnRH Agonists?

Answer 8

•Endogenous GnRH causes increase in LH and FSH (acting on PG), and is therefore a pivotal event in the hypothalamic-gonadal cascade. Can result in oestrus and if there is a follicle may induce ovulation.

Question 9

What are the 2 preparations of GnRH agonists?

Answer 9

–Short-term in action (e.g. buserelin [Receptal] injection) or deslorelin ([Ovuplant] implant)

•Causes stimulation of LH and FSH release

–Long-term in action (e.g. deslorelin [Suprelorin] implant)

•Causes initial stimulation and then receptor down-regulation

Question 10

What are the uses of Short-term in action (e.g. buserelin [Receptal] injection or deslorelin [Ovuplant] implant)? (4)

Answer 10

–Hastening impending oestrus (e.g. Gilts and Sows post weaning / cows in lactational anoestrus)

•(Not in animals that are in seasonal anoestrus)

–Hastening of ovulation within normal oestrus

–Hastening ovulation as part of synchronisation / induction regimes

–Attempting to ‘force’ ovulation of cystic structures

Question 11

What are the uses for long term action of GnRH? (2)

Answer 11

–Causes initial stimulation and the receptor down-regulation

–Licensed use: Control of behaviour and fertility in male dogs

–(Possible use for prevention of breeding in females [common use in zoo animals], or any condition stimulated by GnRH or the lower part of the cascade)

Question 12

What is the GnRH stimulation tets?

Answer 12

•Of course can be used in the male or female to test the hypothalamic – gonadal axis

–GnRH Stimulation Test (commonly short acting preparation):

• Blood sample for sex steroids -> inject GnRH -> repeat blood samples
• Rises in sex steroids confirms functioning pituitary and functioning gonad

Question 13

What is FSH like drug? How does it work?

Answer 13

• Endogenous FSH stimulates follicle growth (may be a way of inducing oestrus in some species)
• In many species eCG is mainly FSH-like in activity

–This is not true in the mare (the reason embryo transfer regimes are not very successful) where it has FSH and LH activity

Question 14

What are the uses of exogenous eCG? (2)

Answer 14

–Ovulation of more follicles than normal when given in early oestrus (superovulation)

•Not in the mare

–As part of oestrus/ovulation induction regimes when given with progestogens

Question 15

How does the LH like drug work?

Answer 15

•Endogenous LH causes final maturation of follicles. Follicle – CL. Speed time of ovulation. Mimic the LH surge.

Question 16

How can we use LH like drug? (2)

•Exogenous hCG (Chorulon) (human – comes from the chorion to support a human pregnancy) mainly LH-like effect

Answer 16

–Attempts to induce ovulation in animals that are in oestrus

• Prolonged pro-oestrus in bitches
• To hasten ovulation in AI regimes (i.e. ensure ovulation occurs when expected)
• Cases of repeated failure of conception in cows and heifers
• Cases of cystic ovaries in cows and heifers

–As part of other more complex regimes to terminate non-seasonal anoestrus

eCG (FSH-like) and then hCG

Question 17

What is the uses of endogenous progesterone? (2)

Answer 17

–Exerts a powerful negative feedback effect upon the hypothalamus/pituitary

–Has effects on target tissues

• Mammary enlargement
• Endometrial proliferation

Effects on behaviour (sedative-like

Question 18

What are the uses of exogenous progestogens? (2)

Answer 18

•Exogenous progestogens (also termed ‘progestagens’)

–Used to suppress the hypothalamic-gonadal axis for control of many conditions

–Used to prevent oestrus

–Dogs, ferrets other species

–Mostly small animals

–Pseudopregnancy in dogs

–(Some male conditions like unwanted behaviour / prostatic disease)

–Used as method of inducing/synchronising oestrus by administration and withdrawal of the product

•Many species often using vaginally placed devices

Question 19

What are the idfferent formulations of exogenous progesterones? (6)

Answer 19

•Oral progestogen tablets (e.g. Megestrol [Ovarid])

–Prevention of oestrus in dogs / suppression of oestrus in dogs

•Progesterone implants (e.g. Etonogestrel [Implanon])

–Contraception in women

•Depot progestogen injections (e.g. Proligestone [Delvosteron])

–Prevention oestrus in bitches

–Long acting prep

•Vaginal sponges (Flugestone [Chronogest])

–Oestrus induction / synchronisation in ewes upon withdrawal (often in combination with eCG)

•Vaginal devices (Progesterone [PRID/CIDR])

–Oestrus induction / synchronisation in mares

•Oral liquids (Altrenogest [Regumate])

–Oestrus suppression / induction / synchronisation in mares/sows

Question 20

How do Progesterone Receptor Antagonists work?

Answer 20

•These products displace progesterone from its receptor but produce no signal

–Progesterone is therefore ineffective although plasma concentrations are normal

Question 21

How can we use progesterone receptor antagonists? (2)

Answer 21

–Stops progesterone from working (the pregnancy preparation drug)

–Only licensed use is termination of pregnancy in the bitch

–But

• Will terminate pregnancy in any species
• Can be used to induce parturition
• Can be used to ‘treat’ conditions stimulated by progesterone (for example pyometra in the bitch / mammary hyperplasia in the queen)

Question 22

How do oestrogens work?

Answer 22

• Quite similar to progesterone (effect on negative feedback)– just it has potent effects on target tissues; bone marrow suppression (Overdose= anaemia and thrombocytopenia)
• Endogenous oestrogens in most species have an effect of potentiating LH surge at ovulation

–They also have significant effects on target organs

• Growth and function of the uterine tube and uterus
• Swelling and tissue development in the vagina, urethra and mammary

Question 23

How may we use oestrogens in clinical practice? (2)

Answer 23

•In clinical practice most oestrogens are given because of their effect upon target organs

–Prevention of implantation (direct effect upon uterine tube and uterine environment) (e.g. Oestradiol [Mesalin] in bitches)

–Control of urinary incontinence (e.g. Estriol [Incurin] in bitches)

•Multiple layers of the vaginal wall and thickening when preparing for pregnancy and this also happens in the urethra!

Question 24

What does endogenous prostaglandin cause?

Answer 24

Lysis of the CL

Question 25

What does exogenous prostaglandis cause? (2)

Answer 25

–Lysis of the corpora lutea although early CLs are usually not responsive

–Smooth muscle contraction

• Uterine = ecbolic effect
• Gut, respiratory tract etc

Question 26

What are the 2 forms of exogenous prostaglandins?

Answer 26

–Synthetic natural PGF2alpha (dinoprost [Lutalyse / Enzaprost])

–Prostaglandin analogues

• Cloprostenol (Estrumate / Planate) (new Product Genestran)
• Luprostiol (Prosolvin)

Question 27

When can we use exogenous prostaglandins?

Answer 27

•Exogenous prostaglandins causes lysis of the corpora lutea although early CLs are usually not sensitive

–Termination of luteal phase and induction of oestrus between day 5 and day 12 (most species except sow [sensitive phase starts later] and bitch [sensitive phase starts later and oestrus not induced as enters anoestrus])

–Time to ovulation depends on follicular wavs

–Only useful for induction in a polyoestrus species

–If you gave to a dog (monoestrus) – you can terminate luteal phase and will just go into anoestrus

Question 28

•Exogenous prostaglandins causes lysis of the corpora lutea although early CLs are usually not responsive

What can we use?

Answer 28

–Termination of luteal phase in a controlled group to synchronise oestrus

–Induction of abortion

–Induction of parturition

–Ecbolic effect

• Treatment of chronic metritis
• Treatment of pyometra (may be CL present depending upon species)

Question 29

What are the ways prolactin inhibitors work?

Answer 29

• In bitches and pregnant queens endogenous prolactin supports the functioning of the CLs (i.e. It is luteotrophic). Causes the behaviour changes e.g. nest building, caring
• Prolactin inhibitors (Cabergoline [Galastop]) remove the support for the CLs therefore progesterone declines. Block the progesterone and end the luteal phase
• Removal of prolactin causes demise of the CL’s; termination of the luteal phase is similar to using PGs but fewer adverse effects and no ecbolic effect

Question 30

When clinically would we use prolactin inhibitors? (4)

Answer 30

–To reduce milk production and behaviour of pseudopregnancy

–To reduce milk after weaning

–To end the luteal phase to terminate pregnancy and treat pyometra

–(To induce oestrus)

Question 31

What are the principels of cycle manipulation? (6)

Answer 31

• Influencing photoperiod or its control
• Mimicking release of gonadotrophins for stimulatory or down-regulation purposes
• Mimicking the action of sex steroids (mainly for the negative feedback effect)
• Lengthening the luteal phase
• Blocking progesterone
• Shortening the luteal phase

Question 32

Complete this table

Answer 32