Treatment Options for Pituitary Dependent Hyperadrenocorticism

By Dr L L van der Merwe , BVSC (MMedVet(Med)

And by dr Marlies Bohm, BVSc DSAM MMedVet(Med) DipECVIM-CA

PDH is the most common (82%) form of canine hyperadrenocorticism. Any treatment whether surgical or medical will require life-long medication and some hormone monitoring

 

A. Surgical resection of the pituitary tumour (trans-sphenoidal hypophysectomy)

Surgery is the treatment of choice for humans. Bjorn Meij of Utrecht pioneered the surgery (trans-sphenoidal hypophysectomy) and has operated on > 200 dogs and cats. With surgery the cause of the problem is addressed whereas with medical management control is aimed at limiting the effects of the pituitary tumour.

If your patient is starting to show neurological signs and the CT/MRI indicate that the tumour is still operable then surgery is really your best choice. If your patient is relatively young you could also consider surgery – because if he is expected to survive for many years assuming his Cushing’s is controlled then it means there are many years for the pituitary tumour to grow and ultimatly causes neurological disease.

There are some pituitary tumours that are too large to be removed. The bigger the tumour the greater the risk associated with surgery and the lower the chance that the tumour can be completely removed.

Dr Meij is prepared to fly out from Utrecht and perform the surgery at Onderstepoort. The post op period is tricky and requires constant supervision in ICU. You will need to cover the costs of Dr Meij’s flights, his professional fee for the surgery and Onderstepoort’s fee. The last case cost the owners approx. R50 000. (Feb 2014). Contact Dr Marlies Bohm (marlies@wol.co.za) if you are considering this option – she organised this for a patient recently.

Prognosis: 

92% of a group of 150 dogs survived surgery and the immediate post-operative period and the survival rates are expected to be even higher in resent cases, as the technique was refined. In 9/150 (6%) dogs the surgeon wasn’t able to remove all  the tumour.

  • In 25% of dogs signs of Cushing’s recurred 6 weeks – 56 months (median 18 months) post operatively.
  • 75% of patients stayed free of signs of Cushing’s and died of unrelated diseases. These dogs lived for an average of 28 months (range 2-87 months) after surgery. This doesn’t sound terribly long, but Cushing’s typically affects middle aged to elderly dogs that have a limited life expectancy in any case.

Post-operative treatment: 

All dogs will need thyroid hormone supplements and hydrocortisone post operatively. The hydrocortisone dose is slowly weaned down to a fairly standard lowest effective dose.

  • The thyroid hormone dose needs to be adjusted to the individual dog.
  • The hydrocortisone dose is increased during times of stress (illness, travel, kennelling, hunting).
  • Dogs may need DDAVP (a synthetic form of antidiuretic hormone, vasopressin) transiently in the immediate post-operative period.
  • Based on 150 operated dogs: 47% of dogs can stop taking DDAVP within 2 weeks of surgery and an additional 31% could stop eventually. The remaining 22% needed it for life.

 

B. Treatment with mitotane (Lysodren = o’pDDD)

Mitotane, the first effective treatment for Cushing’s, destroys the cortisol producing cells in the adrenal gland.  Lysodren is not licensed for use in SA and a section 21 application is required.

Induction : 

Lysodren dose  – 50mg/kg oid

  • Start induction on a Thursday / Friday so that the chances of drama on a weekend are diminished as the process generally takes 5 – 10 days.
  • The pills are given in the morning after breakfast has been eaten.
  • If the dog fails to wolf down his breakfast as normal – then withhold the medication for that day and perform an ACTH stim test (on the same day if possible). Do not administer any further lysodren until you have your results.
  • The target of induction is a post stim cortisol of 25 – 125nmol/L. Unless the dog is showing clinical signs of addisons disease – don’t panic  – you have stopped the treatment and the decrease will flatten out. If the cortisol is <25nmol/L you may supplement with 1mg/kg prednisilone for a few days.  I generally wait 1 week after this sample and then start the weekly maintenance regimen. If the cortisol was <25nmol/L you may want to repeat the ACTH stim to make sure it is in the target range before starting the maintenance therapy  – this may take a few weeks in some cases.

Maintenance: Lysodren 50mg/kg, 1 – 2 x/week

  • Once on maintenance therapy repeat the ACTH stimulation test after 4-8 weeks to see where the maintenance dose is keeping the cortisol. The target once again is 25 – 125nmol/L. I personally find this a bit low  – especially if sampled just prior to next dose (trough level) and am happier with a level between 50 – 150nmol/L. (vdM)
  • Note timing of sampling is important: peak effect (i.e. lowest cortisol) a day or so after dosing, lowest effect (i.e. highest cortisol)  just before next dose. Make a note of this for proper comparison of cortisol levels
  • If your patient is ill /otherwise stressed (e.g. kennelled, going hunting) you may need to supplement low doses of cortisol (prednisone) on those days.

Complications: 

  • Approximately 25% of dogs show one or more adverse effects during induction and approximately 33% develop a sign of overdose at some time during maintenance treatment
  • Overdosing: despite all instructions and counselling, 6-10% of dogs receive excess mitotane and become transiently or permanently Addisonian at some stage in their treatment
  • Gastric irritation: vomiting / diarrhoea may be caused by problems other than the treatment.  Giving the drug with food reduces the likelihood this side effect.
  • Lack of response to treatment: a few dogs have needed > 60 d of daily treatment before their cortisol production decreased. These may do better on trilostane.
  • Sudden expansion of a pituitary mass: Sometimes the pituitary tumour can enlarge and start causing neurological deficits. In some dogs this happens during the induction phase.
  • Liver toxicity: has been reported in some very rare cases.

Response to treatment:

  • The pu/pd and polyphagia usually improves dramatically during the induction phase and normalises in most, not all cases.
  • Weight loss will take some months obviously.
  • It will take some months for the serum chemistry values  to normalise.
  • The skin may take up to 6 month to recover. It may actually get worse for 1-2 months before starting to improve.

Advantages:

  • This is the only medical treatment option if your dog has calcinosis cutis (calcium deposits in the skin) or myotonia (muscle stiffness).
  • You only need to medicate 1-2 x a week
  • It is more cost effective than trilostane

 

C. Treatment with trilostane

Trilostane inhibits conversion of pregnelone to progesterone, a precursor for cortisol and aldosterone – thus both hormone levels are decreased, aldosterone to a lesser degree though. It is licensed in the UK, Europe and USA as a drug called Vetoryl®, which is not available in SA. Several compounding pharmacies produce a trilostane capsules in a variety of sizes.  Around 90% of dogs with pituitary dependent Cushing’s can be well controlled with this drug.

Pharmacokinetics

It is important to understand some of the pharmacokinetics of this compound as it affects amounts dosed, treatment frequency and interpretation of tests monitoring treatment efficacy.

  • Trilostane has low water solubility and an inconsistent absorption which is affected by the formulation. If your patient isn’t responding to trilostane or needs very high doses it MAY be because the drug is not being absorbed properly from the compounded version. If this is the case you could switch to imported Vetoryl and do a Section 21 application.
  • Absorption increases if dosed with meals.
  • The duration of effect varies considerably between patients. Peak plasma levels are reached after 1 .5 – 2 hours and back to baseline at 10 – 18 hours. The drugs is generally active for about 13 hours.
  • Results of the ACTH stimulation test used for monitoring response to therapy varies depending  on time after dosing of the (post pill).
    • The peak drug levels will result in peak effect and maximum cortisol decrease at about 2 hours post pilling.
    • Cortisol levels were higher when the ACTH stimulation test  is performed  4 hours versus at 2 hours post pilling. A current standard is to collect samples 4-6 hours post pilling.
  • Due to a loss of negative feedback during trilostane treatment there is an increase in ACTH secretion, which in turn leads to increase size of adrenal glands in treated dogs
  • Adverse effects  are self-limiting mild GI signs and rarely Addisonian type signs , requiring drug withdrawal and, possibly treatment .The increased endogenous ACTH secretion, especially at the higher starting doses initially recommended,  caused adrenal necrosis. This side effect is much reduced with the lower effective doses utilised these days.

Treatment and Monitoring: 

Initially the recommendations were 2-5mg/kg/day. This resulted in side effects and currently lower doses are achieving good results without the side effects.

  •  1.5mg/kg oid or divided bid in the morning with food. In larger dogs (>20kg) give slightly less than 1 mg/kg.
  • An early 2-week check-up is to make sure the post stim cortisol level is not dropping too low. No dosage increases are made at this time.
  • BID treatment  has been shown to require a lower overall drug dose. Studies show improved survival in dogs treated bid vs those treated oid. Median survival of 900d for bid vs 662 d for oid treatment. Which makes sense if, at best, the drug is only in the system for 13 hrs .
  • In dogs where clinical signs are still present and suppression is in the target range on oid treatment,  bid medication is required as the effect of the drug is too short.
  • In dogs with concurrent diabetes mellitus – trilostane must be used bid from the beginning to reduce insulin resistance.
  • Repeat ACTH stimulation test at 4-6 weeks post initiation of treatment to evaluate the effect of the drug on cortisol secretion. Dosage adjustments can now be made if required.
  • Once the target post ACTH stimulation cortisol range of 50 – 150nmol/L, collected at 4-6 hours post pilling, is reached, monitoring can be done every 4-6 months.
  • If the post stim cortisol value is suppressed to <50 nmol/L then the medication is stopped for a week and restarted without performing and ACTH stim test.
  • If the dog was showing any signs of inappetance, tremors and lethargy concurrently with a low post stim cortisol value then an ACTH stim test is performed prior to re-initiating treatment and treatment is only started again once cortisol levels rise into the target range. For some reason – even though the drug is just an enzyme inhibitor and has a short half-life – its effects can be quite lasting in some animals.

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