Principles of contraception

Question 1

Examples of GnRH agonists

Answer 1

• Buserelin (Receptal)
• Deslorelin (Ovuplant/Suprelorin)
• Gonadorelin (Fertagyl/Ovarelin)
• Peforelin (Maprelin)

Question 2

GnRH agonists (male & female) - actions

Answer 2

• endogenous release causes increase in LH and FSH

Question 3

GnRH agonists (male & female) - types of preparations

Answer 3

Short-term in action
- e.g. Buserelin (Receptal) injection or deslorelin (Ovuplant)
- causes stimulation of LH and FSH release

Long-term in action
- e.g. deslorelin (Suprelorin) implant
- causes initial stimulation an the receptor down-regulation

Question 4

GnRH agonists (male & female) - Long-term in action (e.g. deslorelin (Suprelorin)) - use

Answer 4

Causes initial stimulation and then receptor down-regulation

Licensed use
- control of behaviour and fertility in male dogs
- temporary suppression of oestrus in bitches
- delaying puberty in bitches

Can be used to inhibit reproduction in males and females of all species (dose-dependent).

Implant has 2 sizes

Question 5

Examples of progestogens

Answer 5

• Proligestone (Delvosteron)
• Osaterone (Ypozane)

Question 6

Progestogens - actions

Answer 6

• exert powerful negative feedback effect upon the hypothalamus/pituitary
• central sedative effects (alfaxalone)
• closes cervix
• stimulate endometrial proliferation
• suppress myometrial activity
• mammary enlargement

Question 7

Progestogens - adverse effects

Answer 7

• few in newer generation compounds
• increased appetite / weight gain
• mammary enlargement: benign nodules/neoplasia (except proligestone)
• risk of cystic endometrial hyperplasia -> related to amount/duration of tx
• diabetogenic (insulin antagonism)
• acromegaly
• coat changes esp local reaction following sc injection
• masculinised female pups and cryptorchid male pups if given during pregnancy
• suppression of spermatogenesis

Question 8

Progestogens - use to control oestrus

Answer 8

• prevention = administration in anoestrus to prevent occurrence of oestrus

In bitches for the permanent postponement of heat:
1st injection: in pro-oestrus or in anoestrus
2nd injection: 3m after 1st injection
3rd injection: 4m after 2nd injection
Subsequent injection: at 5 monthly intervals

Alternative is GnRH superagonists

Question 9

Progestogens - treatment of pseudopregnancy

Answer 9

• progestogens inhibit the release of prolactin from the pituitary gland
• depot therapy e.g. proligestone (Delvosteron)

Common alternative is cabergoline (Galastop)

Question 10

Progestogens - in males

Answer 10

Reduction of FSH and LH secretion

LH -> Leydig cells -> androgens
- reduces steroidogenesis
- treatment of:
– antisocial behaviour
– prostate dz
– anal adenoma

FSH -> spermatogenesis
- so the consequence is a reduction of spermatogenesis
- for short term suppression this may be minor but for long term tx this impacts fertility

Question 11

Examples of oestrogens

Answer 11

• Oestradiol benzoate (Mesalin)
• Estriol (Incurin)

Question 12

Oestrogens - actions

Answer 12

• causes oedema of reproductive tract
• pheromone production
• changes in function of the uterine tube and uterus (support sperm transport and the environment for fertilisation) -> stops the pregnancy from being established

Question 13

Oestrogens - adverse effects

Answer 13

• potentiate the effects of progesterone on the uterus -> pyometra
• dose-related bone marrow suppression -> often not given systemically anymore due to this, also risk of pyometra as causing cervix to stay open
  –> anaemia, thrombocytopenia -> death?
• stimulate signs of oestrus
• non-pruritic bilaterally symmetrical alopecia and hyperpigmentation
• if administered during pregnancy may produce abortion

Question 14

Oestrogens - use for unwanted mating

Answer 14

Prevention of implantation and/or interference with transport of zygotes

Licensed preparation is oestradiol benzoate (Mesalin)
- currently not on sale but old product still used in some practices
- Use of d3 & d5 (±d7) post mating

Animals may continue to show signs of oestrus
- may be re-mated
– unlikely to become pregnant

Question 15

Oestrogens - direct effect on reproductive tract

Answer 15

Urinary incontinence
- increase urethral mucosal thickness
- Estriol (Incurin)
– many regimes suggested
– daily for up to 7d then replaced as necessary
– daily for up to 3w
- alternative is Phenylpropanolamine (Propalin)

Topical oestrogens can also be used for vaginitis (overgrowth of commensal bacteria). Thickening of wall of vagina in puberty then can control bacteria that are there. Can be bad if spayed early, affects them later in life
- pre-pubertal
- atrophic

Question 16

Examples of androgens

Answer 16

• Durateston

Question 17

Androgens - use

Answer 17

• mimic the action of testosterone
• anabolics may be used to aid convalescence in some cases
• will induce temporary infertility in males

Question 18

Examples of gonadotrophins

Answer 18

eCG
= equine chorionic gonadotrophin
= FSH-like in action

hCG
= human chorionic gonadotrophin
= LH-like in action

Question 19

hCG - uses

Answer 19

Testing of gonadal function
- e.g. are there any ovaries/testes?
- stimulates the release of oestrogen in female or testosterone in male which we then measure

Hastening of ovulation
- female has to be in oestrus with large follicles that are capable of responding i.e. they have to have LH receptors

Forcing of ovulation
- e.g. in cases of follicular cysts, but again follicles will only respond if they have LH receptors

Question 20

Prostaglandins - endogenous vs exogenous prostaglandins

Answer 20

Endogenous prostaglandin causes lysis of the CL

Exogenous prostaglandins cause
- lysis of the CL although early CLs are usually not responsive
- smooth muscle contraction
– uterine ecbolic effect
– gut, resp tract, etc

Question 21

Prostaglandins - 2 forms of exogenous prostaglandins

Answer 21

Synthetic natural PGF2a
- dinoprost (Lutalyse / Enzaprost)
- luteolytic and spasmogenic effects

Prostaglandin analogues
- Cloprostenol (Estrumate / Planate)
- Luprostiol (Prosolvin)
- generally analogues have fewer smooth muscle effect cf luteolytic effects
- less spasmogenic -> less bronchial contractions causing respiratory signs, gut contractions causing nausea + d+, but also removes contraction of uterus

Question 22

Prostaglandins - actions

Answer 22

• lysis of CL
• early CLs are usually not responsive
• ecbolic: smooth muscle contractions limited -> useful for expulsion of material in cases of metritis
• induce labour or reduce post-partum haemorrhage

Bitch & queen CL are ‘autonomous’ for 1st 14d of luteal phase
- PGs of little use before d20

Remaining luteal phase CLs remain resistant
- need frequent dosing every day or 2x daily

Pituitary increases prolactin in response to falling progesterone which may cause signs of pseudopregnancy

Question 23

Prostaglandins - adverse effects

Answer 23

• restlessness
• hypersalivation
• v+
• abdo pain
• d+
• pyrexia

Question 24

Prostaglandins - use for tx of luteal phase conditions

Answer 24

Open-cervix pyometra
- low doses 2x daily for 5-10d
- fluid therapy
- suitable antimicrobials

Termination of pregnancy
- low doses 2x daily for 5-10d
- commence after d20
- termination by resorption or abortion

Generally this use is largely superseded by combinations of prolactin inhibitors with prostaglandins

Question 25

Prostaglandins - use for tx of non-luteal phase conditions

Answer 25

Post-partum metritis - low doses 2x daily for 3-5d - fluid therapy - suitable antimicrobials Here prolactin inhibitors have no value

Question 26

Oxytocin - use

Answer 26

- contraction of uterine smooth muscle when receptors are present -- oxytocin receptors decrease rapidly after parturition - pharmacological contraction of uterine smooth muscle when few receptors are present - milk 'let-down' in cases of agalactia - stimulation of uterine contraction to facilitate parturition in the presence of a fully dilated cervix -- low dose regimes are required so not to cause titanic contraction -- 0.04IU/kg given every 30mins for 3 doses - promote involution of the post-parturient uterus and thus aid the passage of retained placenta - aid in the control of post-partum haemorrhage

Question 27

Oxytocin - adverse effects

Answer 27

- don't administer if the cervix is closed or in cases of obstructive dystocia

Question 28

Prolactin - uses

Answer 28

- increases from approx d25 after ovulation - the principle luteolytic agent in the bitch and queen - other action is to promote stimulate milk production

Question 29

Prolactin agonists - use to stimulate milk production

Answer 29

Prolactin agonists are dopamine antagonists - metoclopramide at 0.1-0.2mg/kg SC TID-QID - phenothiazines at low dose may also stimulate mild production

Question 30

Prolactin inhibitors - what do they do?

Answer 30

- removal of prolactin causes demise of CLs - progesterone rapidly declines - termination of luteal phase is an action similar to using prostaglandins but: fewer (different) adverse effects and no effect on the uterus - no effect in the early luteal phase - not actually luteolytic but is luteotrophic, so removing it makes the CL phase and ends the luteal phase - end pregnancy, treat pyo, treat pseudopregnancy - suppression of lactation e.g. post weaning

Question 31

Example of prolactin inhibitor

Answer 31

Cabergoline (Galastop)

Question 32

Prolactin inhibitors - adverse effects

Answer 32

- nausea & v+ - lethargy - (abortion) - (return to oestrus)

Question 33

Prolactin inhibitors - off licence uses

Answer 33

- to end the luteal phase to terminate pregnancy (often done in combination with prostaglandin) - to end the luteal phase to treat pyometra (often done in combination with prostaglandin) - to induce oestrus: if prolactin inhibitors given on a regular basis (mechanism unknown)

Question 34

Prolactin inhibitors - use for tx of pseudopregnancy

Answer 34

- daily tx for 5-7d - if not complete response then continue tx period - recurrence uncommon unlike following progestogens

Question 35

Prolactin inhibitors - use for termination of pregnancy

Answer 35

- tx with prolactin inhibitor from 25 days after ovulation onwards as earlier tx ineffective - tx at 28-35d causes pregnancy loss by resorption - tx commencing after d35 causes pregnancy loss by abortion - tx efficacy increased by concomitant use of PG -- cabergoline 5mcg/kg/day for 10d combined with cloprostenol 2.5mcg/kg every 2nd day on 5 occasions - tx >95% effective when commences at d28 - always confirm pregnancy termination using US

Question 36

Prolactin inhibitors - use for tx of pyometra

Answer 36

- aim is to remove progesterone and stimulate uterine contractions - prolactin inhibitors cause a decline in progesterone - prostaglandins cause a decline in progesterone and uterine contractions - cabergoline daily at 5mcg/kg combined with cloprestenol every 3rd day at 2.5mcg/kg -- can be used for closed cervix pyometria if prostaglandin delayed until d3 i.e. when it is open-cervix pyometra - tx over at least 10d - ensure cure using US of the uterus, or continue to tx until there is no further discharge If given in a closed pyo this might result in a tear in the uterus. Prostaglandins not recommended in closed pyo. Only give prostaglandin when cervix open (discharge) after giving galastop -> converts closed to open pyo

Question 37

Prolactin inhibitors - use for induction of oestrus

Answer 37

- cabergoline at 5mcg/kg/day - tx given daily until 1d after onset of proestrus

Question 38

Progesterone receptor antagonists - example & what it is

Answer 38

- aglepristone (Alison) - synthetic steroid which binds to progesterone receptor - affinity for receptor 3x higher than progesterone - outcome is receptor binding but without any message - progesterone cannot bind to its receptor -> essentially progesterone becomes 'invisible' and not effective

Question 39

Progesterone receptor antagonists - adverse effects

Answer 39

Local tolerance - 9% of bitches have injection site reaction in 1 of the 2 injection sites - resolve within 2-8w - always use at least 2 injection sites (more in large bitches) CS typical or normal parturition

Question 40

Progesterone receptor antagonists - potential uses

Answer 40

- prevention of implantation - termination of pregnancy at any stage - tx of pyo (off license)

Question 41

Progesterone receptor antagonists - use for tx of unwanted mating up to 20d after mating

Answer 41

- 2 doses 24h apart - no CS -- appears as though never pregnant -- remember 50% probs weren't pregnant anyway

Question 42

Progesterone receptor antagonists - use for tx of pyometra

Answer 42

- multiple repeated doses - cervix relaxes and uterine fluid expelled - few studies performed -- some show subsequent fertility -- advantages over PG-Prolactin antagonist regimes?

Question 43

Melatonin in females

Answer 43

- endogenous production in response to decreasing daylight - up-regulation of short-day breeders - down-regulation of long-day breeders

Question 44

Melatonin - use in ewes

Answer 44

- melatonin implant administered at base of ear in May-June to hasten onset of cyclicality (+ introduction of the ram) = earlier pregnancy so born earlier e.g. xmas so easter slaughter

Question 45

Melatonin - use in queens

Answer 45

- off-label administration of Melatonin will suppress oestrus temporarily Used as some benefits over alternatives - GnRH agonists longer acting - progesterone can cause uterine dz and subsequent infertility

Question 46

Surgical sterilisation - advantages

Answer 46

- reduction in the incidence of mammary neoplasia - prevention of uterine dz including CEH, pyo and uterine neoplasia - prevention of ovarian dz including neoplasia - prevention of endocrine dz such as pseudopregnancy

Question 47

Surgical sterilisation - disadvantages

Answer 47

- increased incidence of urinary incontinence in dogs? - changes in coat texture? - tendency to gain weight? - changes in behaviour? - increased incidence of some neoplasia -- in some breeds there is a clear relation the longer that ovaries or testes are present the lower this risk

Question 48

Advantages of ovariectomy over ovariohysterecomy

Answer 48

- simpler - less traumatic - faster - more rapid recovery - cheaper - fewer surgical risks (may include less urinary incontinence) - more amenable to laparoscopic sx

Question 49

Ovariectomy - leaving the uterus will not result in uterine dz unless...

Answer 49

- the uterus was already abnormal - you leave an ovarian remnant - there is a neoplasm producing reproductive steroids (eg. adrenal possible but rare) - exogenous reproductive steroids are administered Reasons for administration of reproductive steroids - progestogens for skin dz - oestrogens for urinary incontinence - may cause uterus to enlarge and pathologies to develop

Question 50

Surgical contraception in bitches

Answer 50

Traditional options - OHV or OV (OV can be performed laparoscopically) More recent considered of hysterectomy ('ovarian sparing spay') - based on information about the life-time risks of removal of the ovaries (increased risk of certain neoplasia) that is changing perceptions -- much of this may be associated with supra-physiological concentrations of LH causing neoplasia - but don't forget the significant advantages of neutering (behaviour, elimination of pregnancy and ovarian & uterine dz)

Question 51

When to spay the cycling bitch?

Answer 51

Preferably greater than 12w after oestrus so you don't induce an iatrogenic pseudopregnancy - between w4-12 pituitary is producing prolactin - if you remove progesterone by spaying her in this time she will continue to produce prolactin Or within 3-4w post oestrus before prolactin is turned on so you don't induce pseudopregnancy Can spay in pro-oestrus or oestrus but surgery is trickier due to more oedematous/vascular reproductive tract

Question 52

Surgical contraception in dogs

Answer 52

- traditional procedure is castration - but recent evolving information about the life-time risks of castration (increased risk of certain neoplasia) is changing perceptions - significant advantages of castration (behaviour and elimination of testicular and most prostatic dz) Now considerations of - causing testicular damage ('hormone-sparing castration') -- intra-testicular injection: not licensed in UK -- does this really work?? - no surgery - vasectomy -- stops sperm going down the vas deferens -- becomes infertile but depends on degree of sperm storage in the ampulla

Question 53

Behaviour after surgery

Answer 53

- hormone concentrations decline quickly after castration however some behaviours is learned and in some cases libido may be retained for years if castrated after puberty - no change in hormone concentration after vasectomy

Question 54

Infertility after surgery

Answer 54

Onset of infertile ejaculate will depend upon the degree of sperm storage in the ampulla - dogs have very small ampulla therefore azoospermic within a few days - stallions have a significant ampulla (dilated part of vas deferens) therefore sperm may be detected for severe weeks or until he ejaculates

Question 55

Decision making for any male or female for contraception

Answer 55

- is permanent or temporary solution required? - is this for an individual or groups of animals? - animals age, concurrent dz status? - what are the possible adverse effects of different regimes and are these tolerable? - what are the ethical considerations of both surgical and medical solution? if for temporary contraception - is this likely a future breeding animal? - what is their current age? - how many tx will be required over lifetime? - what is the total cost?

Question 56

Incomplete ovariectomy - how do these cases present?

Answer 56

- oestrus behaviour occurs at the normal interval with subsequent normal cyclicity - oestrus behaviour is absent for several months to years and is then normal, weak or persistent and may or may not be followed by normal cyclicty - oestrus behaviour is absent for many years until persistent weak behaviour associated with a granulosa cell tumour is detected

Question 57

Incomplete ovariectomy - diagnostic tests

Answer 57

Observation of behaviour - may show standing oestrus behaviour and tail deviation - may allow mating - may show swelling of the vulval and perineal tissue - may have vulval discharge (may be serosanguinous if uterine tissue remains) Vaginal cytology and vaginoscopy - can detect proestrus and oestrus - large nuclear vaginal epithelial cells in the vaginal smear and usually low numbers of polymorphonuclear leucocytes -- % of both cell types depends on exact time of presentation - vaginoscopy will reveal a moist, swollen and oedematous epithelium that is pale in colour - vaginal cytology and vaginoscopy aren't able to differentiate a bitch with IO that is in the luteal phase from a bitch with no ovaries US of ovaries - may detect if animal not obese Measurement of progesterone - elevated for 65d after ovulation so only useful then Measurement of oestrogen - difficult - elevated in protestrus / early oestrus but declines in mid oestrus and thereafter will be low - only elevated oestrogen concentrations are diagnostic Stimulating the ovary to produce oestrogen (give either GnRH or hCG) - works best when the dog is in anoestrus Measurement of anti-Mullerian hormone - has some false positive and false negative results Measurement of LH - removal of gonads means LH will be very high but difficult to measure

Question 58

Incomplete ovariectomy - how to investigate

Answer 58

Establish when last alleged oestrus was observed Think: if it had an ovary when would it be in cycle, then categorise the dog like this: - is currently showing proestrus or oestrus -- i.e. is she in oestrus or is she spayed? - is within 2m after alleged oestrus -- i.e. is she in the luteal phase or is she spayed? - is more tan 2m after alleged oestrus -- is she in anoestrus or is she spayed?

Question 59

Incomplete ovariectomy in the queen

Answer 59

- generally cycle every 2-3w Simplest approach is to examine when they're in alleged oestrus: Observation of behaviour and CE - queens that have IO and are in proestrus/oestrus have behavioural changes that differentiate them from queens with no ovaries and these include: vocalisation, treading, rolling, tail deviation and lordosis - these queens may allow mating - CE may also reveal swelling of the vulva and perineal tissue and a mucoid vulval discharge Vaginal cytology - queens that have IO and are in proestrus/oestrus have large vaginal epithelial cell in the vaginal smear (but these may not be anuclear as in the bitch) and usually low numbers of polymorphonuclear leucocytes - the % of both cell types depends on the exact time of presentation US Measurement of plasma progesterone concentration - progesterone will be low in proestrus and oestrus, and will not rise at the end of oestrus unless the queen is induced to ovulate - administration of GnRH or hCG will stimulate ovulation and a rise in progesterone which can readily be detected by blood sampling 1-2w later when the queen is in the luteal phase Measurement of plasma oestrogen concentration - oestrogen is elevated in proestrus / early oestrus but declines in late oestrus and thereafter will be low - only elevated oestrogen concentrations are diagnostic Stimulation of oestrogen production with GnRH or hCG - false positives and negatives Measurement of plasma anti-Mullerian hormone (AMH) Measurement of resting LH - although LH is low in queens with IO and elevated in queens with no ovaries, if the queen with IO presents in proestrus/oestrus LH concentrations may be elevated and so the test is not diagnostic at this stage