From:
"Sukie Crandall"
Date: 2007-09-04 04:09:07 UTC
Subject: [ferrethealth] Re: Prophlactic Lupron treatment?
To: ferrethealth@yahoogroups.com
The quoted message below is from Dr. Cathy Johnson-Delaney.
I wrote to her because she is one of the people whose work
relates to the post on the other site.
The only change I have made is spacing (shortening the lines) so
that we don't wind up with those long then short length lines that
Yahoogroups can cause.
The work on melatonin becoming refractory was by Dr. Jack Oliver
of Tennessee and Dr. Nico Schoemaker of the Netherlands.
Dr. Johnson-Delaney asked me to preface this with
"this is what we know to date"
BEGIN QUOTE OF DR. JOHNSON-DELANEY
Hi - thank you for contacting me. We are in the process
of publishing a great deal of data on many aspects of the
hormonal control of adrenal disease, hormonal cycles, values
of intact animals, lupron trials, and the hormonal values
throughout the first year of the early spay/neuter animals
compared with intact age matched sex matched counterparts.
I have already published a controlled study using the melatonin
implants in intact male ferrets in season: it did not control their
hormone levels. Dr. Nico Shoemacher has published a number
of papers looking at the hormonal controls on the receptor-site
level. He and Dr. Michele Hawkins just presented the up to date
information on adrenal disease at the Assoc of Exotic Mammal
Veterinarian's conference. All veterinarians who see and treat
ferrets should receive the Journal of Exotic Pet Medicine, the
journal of the Association of Exotic Mammal Veterinarians; and
Exotic DVM. These are the 2 publications which contain the most
current information on adrenal disease and its research findings.
I have presented and published a number of papers over the years
which appear in both of those journals, along with meeting
proceedings.
I do not know what was presented at NAVC. I have seen no data
looking at melatonin with lupron. I do not know of any study using
220 mg of lupron. That is a value that doesn't make sense given
that you need to specify sex, what type of lupron (30 day, 3 month
or 4 month) is used.
Our current state of knowledge as presented by Drs Shoemacher,
Hawkins & myself (ended up doing a great deal at the AEMV wetlab
at the beginning of the conference teaching ultrasound on ferrets -
all ferrets we had from shelters had adrenal and other pathology) is
1. The spay/neutered ferret continues to have "hormonal cycles" just
as if it were intact.
2. Suppression of the pituitary at the beginning of puberty/first
reproductive season is the crucial time for stopping that first major
stimulation to the adrenal glands. In northern US (Seattle), males
(intact, puberty, early spay/neuter) have their highest sex hormone
values very late Dec through Jan; females late Jan through Feb. This
may be different in different latitudes.
3. The ferret brain never knows that it has been neutered, therefore
at each reproductive season, suppression of the LH surge and
subsequent sex steroid production and adrenal sex steroid
production stimulation may slow the onset of adrenal disease.
4. Melatonin does not suppress the key hormones particularly at
certain times of the year, ferrets become refractory to it, it does
not slow tumor growth, and its main function is cosmetic: hair
growth. In some it causes a toxicity. Bottom line: response and
decrease of symptoms may be short-lived, although it is
advocated due to the fact it is cheaper and some veterinarians
erroneously measure adrenal disease only with haircoat.
5. Studies with lupron 30 day depot formulation, 100 mcg for females,
200 mcg for males have proved that 1. its effects last 30 days in
intact ferrets in season (highest hormone levels and cycle to control -
it controlled it very well - melatonin didn't); It is superior to
decreasing hormone levels in ferrets with adrenal disease to
pre-adrenal, very low levels until the tumor is beyond pituitary control;
It slows the progression and growth of the adrenal tumor at least in
early stages, and in some this translates as years; ferrets in a controlled
study of lupron vs unilateral adrenalectomy: lupron alone was superior
to unilateral or partial adrenalectomy as uni/partial adrenalectomy
triggers a rebound of hormones higher than originally; lupron plus
adrenalectomy led to slightly longer lives in the males; females
receiving lupron alone lived longer than females having surgery. All
ferrets who receive adrenalectomy need to concurrently have hormonal
suppression to live the longest, the difference in surgical outcome was
in the males since the prostate enlargement frequently is the
life-limiting factor in males, not the size of the adrenal tumor itself.
6. The controlled study of the 3 month lupron given to intact males
and females in season (Jan-May) in Seattle: worked in the males for
nearly 3 months; several females returned to heat at 60, 75 and 80
days. Dosage was prepared as appropriate by working with the drug
manufacturers to determine dosage: 0.9 mg. Larger dosage would not
do any better as Lupron in any form depends on tissue enzymes to
break it down, thereby limiting length of time it lasts in the muscle.
As 3 month lupron is exorbitantly expensive, and if the 30 day lupron
is fresh, frozen for no more than 1-3 months, and dosages are not
missed, there has been no "refractoriness" to it in the 10 years I have
been using this drug in ferrets on a monthly basis. Some ferrets on the
study received monthly lupron for nearly 4 years with effectiveness until
the tumor was beyond pituitary control. Dr. Hawkins' research group at
UC Davis is doing some potency studies and work on lupron itself - they
have looked at a number of doses sold by compounding pharmacies and
found these do not contain the appropriate dosage; looked at how long
it retains potency frozen in regular freezers when reconstituted with
sterile water: starts breaking down, but potency should be reasonable
for at least a month. Note: at my clinic and the Washington Ferret
Rescue none of our lupron used is over 30 days from mixing and
freezing - usually considerably less time. We go through over 150
100 mcg doses a month. We have not seen refractoriness or lack of
effectiveness with this drug even used for more than 3 years monthly.
7. The Univ of GA had been using 2 mg of the 4 month lupron per
ferret but noticing breakthrough hormone and symptom returning by
3 months. I have not done any controlled studies looking at the actual
length of time it works in intact ferrets in season, again, as the cost of
this is exorbitant.
8. Dr. Shoemacher has been working with another human sex steroid
hormone suppressor that may be the drug of the future for control. It
is an implant, but currently unavailable for use. We also have a lot of
questions on its use still to be answered as to duration of action, how
well it suppresses, etc. But it looks very, very promising. Stay tuned.
9. Many ferrets particularly those with enlarged prostates along with
lupron need additional (usually short-term) peripheral hormone
blocker drugs such as bicalutamide, finasteride, anastrozole, etc. The
only way to determine this is to watch hormone values, sizes of glands,
etc. Many of the "failures" of lupron treatment have been because
1. stage of the disease was not diagnosed when the ferret was first
presented - I.e. treatment totally based on haircoat!, not sex steroid
values, size and pathology of the adrenal glands, etc. 2. lupron was
improperly compounded or stored or was old (I.e. more
than 3-6 months frozen) or improper dosage given (like 100 mcg to a
large male!) or dosages were erratic and skipped (not given every 30
days). Sometimes it takes 2-3 dosages to build the controlling hormone
plateau (GNRH) which is necessary to stop the release of LH that in turn
stops the stimulation to either the gonads or the adrenals to
manufacture sex hormones). Failure of medical treatment is also seen
when it is started late in the disease after surgery - the rebound high
hormone levels I've found are hard to control and the remaining adrenal
tissue is malignant, grows faster, and is no longer controlled by the pituitary.
3. Season of the year the ferret is presented: it is harder to control
females hormone levels in the spring - you may have to use a higher
dose of lupron initially plus a peripheral estradiol blocker; its harder to
control males in January - you may need to use a higher dose or what I've
found works better is do a second lupron at 15 days in January - but
seasonal levels may be different in latitudes so this timing is what we
found in Seattle. The same 3 yr studies I did with intacts,
neutered/spayed at puberty, and early spay/neuter need to be repeated
in the south. Note: vets in Fl and Tx have had better luck with putting
the ferrets in the dark and some claim the melatonin once as they have
a much higher intensity of light and heat that we do up here. Studies done
in the early 70's though showed that ferrets kept in the dark initially came
into estrus and reproductive season anyway - they were just out of synch
with the calendar and natural cycle. So again, altering the light cycle may
help a little, but for pet owners, its really not practical nor does it seem
to work long term.
10. Based on how adrenal stimulation, the endocrine system, intact vs
early spay/neuter hormone patterns, seasonal cycles we hypothesized
based on research and also the neuroendocrine work done in the 60's,
70's, and early 80's with ferrets: if we suppress the initial hormone surge
and build up that occurs every springtime (beginning of repro season) we
may be able to trick the ferret's pituitary into thinking 1. it is an intact
ferret going into puberty the first year, regular reproductive season each
subsequent year 2. chemically force the pituitary to trigger the hormonal
surge then plateau that shuts off the stimulation for more production of
sex steroids - essentially causing a chemical "breeding" which in turn
because ferrets are copulatory ovulators with seasonal controls--takes
them out of breeding season. In Seattle, from 5 years of hormone tracking
in intacts, neutered at puberty and early spay/neuter, we didn't need to
do it a second time. In southern latitudes - I don't know if they have
a natural "second" season or breeding that would need a second
chemical suppression - this is why my studies need to be repeated in
the south. Based on the way adrenal disease starts, suppressing or
blocking that initial stimulation and then each subsequent year should
slow the onset (Dr. Shoemacher has proved a correlation from the time
of neutering until the onset of disease - largely because the natural
control cycle is interrupted).
So based on all of the above, 4 years ago we started a small study to do
just that: a chemical breeding at the first puberty and then annually
block the seasonal stimulation - using lupron 30 day depot formulation.
100 mcg for the females, 200 mcg for the males, delivered
intramuscularly. We have over 50 ferrets we have now been doing this with
- some are close to 5 years of age, the bulk are 3 years old. We have no
adrenal disease in these so far. Time will tell. But we do know that in a
group of 50 early spay/neutered ferrets without any intervention - it is
likely that several would already have adrenal disease.
1. Does it do any harm to give a lupron injection that first season at
puberty and every subsequent year at the beginning of breeding season?
NO.
2. Will it slow the onset or prevent adrenal disease until the ferret is very
old? We don't know yet, but it is looking promising.
3. Is lupron (leuprolide acetate depot 30 day formulation, sold in kits
of either 3.75 mg or 7.50 mg) the best drug we have to control the
pituitary, the progression, and the symptoms associated with adrenal
disease? Currently, yes if mixed properly, stored properly, and given
properly on schedule.
4. Are other drugs being investigated in good, controlled studies
(not anecdotal by symptoms only)? Yes. Watch the above journals and
conference of the Association of Exotic Mammal Veterinarians for the
breakthroughs and new information as it happens.
5. Are symptoms alone (I.e. hair coat, behavior) adequate to diagnose
and manage adrenal disease? NO. Do properly manage the disease and
buy the ferret its 5-7 year life span with a good quality of life, hormone
levels, ultrasound, maybe surgery, regular medical checkups (especially
to keep any other diseases from becoming major problems) are necessary.
The two times of the year I like to measure hormone levels in adrenal
ferrets to see how well we're managing it are the high time (Jan for males,
Feb-Mar for females) again, Seattle, may be different other parts of the
country; and the low time (Aug-Sept for males; late Sept-Oct for females).
If hormones are out of control in what should be the low point, you need
to change your management therapy. If hormones are in control in the
High time, the disease is being managed. These two times can be crucial
to adjusting therapy.
So: what do I recommend to my ferret owners? I discuss the above with
them, and many are opting to try the suppression. If it even delays onset
by a year - that is helpful. For those with kits - definitely I try to have
them get lupron at seasonal puberty. But we are honest in telling them
that we don't have all the data and that it will take time. We cannot
guarantee that it will stop it.
Please remember that it was only in September of 1996 that lupron was
first used in a ferret (Robbie McFerret Delaney) with adrenal disease: he
died after 11 months with the adrenal disease fully controlled, but due to
islet cell carcinoma at age 7.5. After his necropsy and histopathology, I
began using lupron on other ferrets and Drs. Susan Orosz, Jack Oliver
and myself along with help from the Washington Ferret Rescue & Shelter,
and TAP Pharmaceuticals (provided the first study lupron) began the
controlled studies. The data is still being statistically analyzed (I've gotten
help from the Univ of TN) but as a busy practitioner, I have not gotten it
published yet in refereed, research journals. Dr. Shoemacher has gotten
his work on LH receptors, age of onset of adrenal vs time of neutering,
etc. published, but is also still working on this disease, as is Dr. Hawkin's
and her group at UC DAvis: they are looking at possible genetic controls
of tumors. The 6 study early spay/neuter ferrets live at my house and
work is continuing following them - 2 are on lupron monthly, all get it
annually, but I may have missed that really crucial first puberty time
point with them as we didn't know then what was happening with the
hormone levels. These ferret's hormones were higher than their age/sex
matched intact counterparts! Difference was that the intact ferrets'
cycle out as the weather got warmer - the early spay/neuter ferrets
stayed high. Time will tell, as it will with the ferrets we are trying the
pre-emptive lupron per breeding season.
I also urge you to have your readers be sure their veterinarian is
receiving the current publications specifically dealing with ferrets
and exotics, as the main dog/cat general literature is inadequate
in addressing ferrets and specifically new developments. Your
veterinarian should be receiving current continuing education in
ferret medicine at some of the major conferences, specifically to
stay on top of new developments, the Assoc of Exotic Mammal
Veterinarians annual conference. It will be held next year again
in conjunction with the Association of Avian Veterinarians, in
Savannah, Georgia in August 2008.
I hope this clarifies things.
Cathy Johnson-Delaney, DVM, DABVP-Avian
President, Association of Exotic Mammal Veterinarians
Eastside Avian & Exotic Animal Medical Center
13603 100th Ave NE
Kirkland, WA 98034
425-821-6165; toll free 888-821-6165
www.avianexoticmedcenter.com
fax: 425-821-6130
Support the Ferrets: www.washingtonferret.org
END QUOTE
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