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Highlights

Section 2 mentions that melatonin is often used as a first treatment.

Section 8 below mentions using lignans along with ketaconazole.

Section 5 mentions using lignans in conjunction with Lysodren.


Treatment Option Considerations
Steroid Profiles in the Diagnosis of Cushing’s Disease
Clinical Endocrinology Service/College of Veterinary 
Medicine/University of Tennessee

Where positive test results of increased adrenal activity are present, consider the need for:
1)        Ultrasound and/or Endogenous ACTH.  Procedures to rule out primary adrenal 
tumor presence.
2)        Melatonin.  Often used as a first treatment, especially if alopecia is present, since it 
is cheap, has few side effects and is available in health food stores or via nutrient 
suppliers on the Internet.  Typically, a dose of 3 mg is given every 12hrs  for dogs <30 lbs; 
a dose of 6 mg is given every 12hrs  for dogs >30 lbs.  Regular melatonin is usually used 
rather than rapid release or extended release products.  Melatonin has anti-gonadotropic 
activity (effective for ferret adrenal disease), and it inhibits aromatase enzyme in tissues 
(decreases androstenedione and testosterone conversion into estradiol) and 21-
hydroxylase enzyme (effectively lowers cortisole level).  Allow at least 4 months for 
treatment effects to be effective.  Response time is variable between dogs.  Monitor 
treatment effectiveness by improvement in clinical signs, biochemistries or by repeat of 
steroid profile.
3)        Melatonin Implants.  Available for dogs and ferrets.  (WWW.MELATEK.NET).  Sizes 
are 8, 12 and 18 mg for <25, 25-50 and >50 lb dogs, respectively.  Effects last 3-4 
months.      Note:  Melatonin and flax hull product with lignans are used together when 
estradiol is increased.  
4)        Lignan.  Lignan has phytoestrogenic activity, and competes with estradiol for tissue 
estrogen receptors, with less biological effect.  Lignan also inhibits aromatase enzyme 
(lowers estradiol) and 3-beta HSD enzyme (lowers cortisol).  Use either FLAX HULL (SDG) 
lignan, or HMRlignan.    DO NOT USE flaxseed OIL as the lignan content is very low, and 
the flax oil can increase triglycerides.    
Suggested doses:  SDG lignan; one milligram/lb B.  Wt./day.  HMRlignan; 10-40 mg/day for 
small to large dogs.  
5)        Maintenance dose of LysodrenTM.  Often useful in combination with melatonin and 
lignan to help lower sex steroid levels other than estradiol, along with suppressive effect 
on cortisol level.  NOTE: MONITOR CORTISOLE LEVELS ARE FOR TYPICAL CUSHING’S 
TREATMENT.
6)        LysodrenTM, traditional treatment for Cushing’s disease. Very effective in lowering 
cortisol, progesterone, androstenedione and 17-hydroxyprogesterone levels.  NOTE: 
Estradiol is not always suppressed by LysodrenTM.  A baseline estradiol level 1 month 
post-Lysodren will determine efficacy.
7)        Trilostane.  Now available in the U.S. as Vetory1TM from Dechra Veterinary Products.  
NOTE: Trilostane always increases 17-hydroxyprogestone (some cross-reactivity with 
pregnenolones in assays??), and frequently increases estradiol and androstenedione as 
well.  LysodrenTM  may be preferred for Atypical Cushing’s cases.  FURTHER NOTE: Care 
should be used in switching from Trilostane to LysodrenTM.  Allow adequate time for either 
drug’s effects on the adrenals to subside before switching treatments.  (E.G., one month 
off drug; normal or increased stim-cortisol levels).
8)        Ketoconazole.  Cushing’s disease treatment.  Effective for increased cortisol and 
sex steroid levels.  Consider 6 to 12 mg/kg, BID along with melatonin and lignan as 
above.  See write-up at our website (and the recent article on the ketoconazole treatment at 
JAVMA, 233:1896,2008).
9)        Selgiline (AniprylTM).  A less used alternative Cushing’s disease treatment.  See 
Plumb’s Formulary.
10)        Hormone cream exposure.  Products may contain 
estrogen/progestines/testosterone; may result in high serum levels of estradiol and 
progestins, as well as nipple, vulva, and clitoris enlargement.
11)        Ovarian remnant detection.  hCG stim test (estrus) and measurement of 
progesterone is indicated.
12)        Retained testicle detection.  hCG stim test and measurement of testosterone is 
indicated.
13)        For clarification regarding test results, Contact Dr. Jack Oliver (865-974-5729; 
joliver@utk.edu).  Also Dr.’s. Kellie Fecteau or Hugo Eiler are available in Dr. Oliver’s 
absence.  (865-974-5638).  Note: Several patterns of hormone increase occur, so doing 
the complete adrenal panel is advised.
14)        For further information on our Service (e.g., submission, shipping, protocols, 
treatment, review articles) see our website (www.vet.utk.edu/diagnostic/endocrinology).  
Revised 05-01-10 (JWO).


LIGNANS (PHYTONUTRIENTS

Source.
Currently, there are two types of lignans on the market:
1) Flax hull (SDG) lignans derived from the hulls of flax seed; and lignan that is derived 
from the Norwegian Spruce tree (HMRlignan).  Extensive discourse on these two product 
types can be found by Googling the Internet.

Active Ingredients
SDG flax hull lignan.  The major active ingredient of flax hull (SDG) lignan is 
secoisolariciresinol diglucoside (thus, SDG).  SDG flax hull lignan is metabolized by 
intestinal bacteria to enterolactone (the major active mammalian lignan that is found in 
body tissues), and also enterodiol (also a mammalian lignan).  Both enterolactone and 
enterodiol are formed in the gastrointestinal tract by bacterial breakdown of the consumed 
SDG lignan.  The process involved with SDG lignan is a two-step procedure that delays 
absorption time (www.organic-herb.com).  But the usual doses used appear to give 
adequate levels of enterolactone for 24 hours on a once-daily-dosing basis.
(www.lpi.oregonstate.edu/infocenter/phytochemical/lignans).
HMRlignan.  The active ingredient of HMRlignan is different from that of SDG flax hull 
lignan and is 7-hyroxymatairesinol (thus, HMR).  HMRlignan is extracted from the 
Norwegian Spruce tree, and yields high amounts of  HMRlignan.  Once ingested, it is 
directly converted by gastrointestinal bacteria into the major-endogenous-mammalian 
lignan (enterolactone).  HMRlignan forms more enterolactone than SDG flax hull lignan, 
since another endogenous-mammalian lignan called enterodiol, is formed by SDG lignan, 
and is less bioactive in systemic tissues compared to enterolactone.  Cleavage of sugar 
chains must occur for SDG flax hull lignan, by the intestinal bacteria, before the 
mammalian lignans are formed.  This may or may not offer efficacy advantages to 
HMRlignan (further research will be needed to prove or disprove this).  Blood levels of 
HMRlignan remain adequate for 24 hours on once-daily-dosing.  HMRlignan reportedly is 
readily and completely absorbed from the gastrointestinal tract (SDG lignan is not 
completely absorbed, although adequate blood levels do occur from dosages used).  
Thus, better bioavailability and more rapid uptake occurs for enterolactone formed from 
HMRlignan.  Since HMRlignan’s bioavailability to the body is better than SDG flax hull 
lignan, this allows reduced doses to be used.  

Adverse Effects.
SDG lignan, having fiber as a component, can cause increase in stool frequency (and 
occasionally diarrhea).  HMRlignan contains very little (if any) fiber, so this side effect 
should not be seen with HMRlignan.

Safety.
No adverse side effects to the use of SDG flax hull lignan have been reported to our lab, 
based on suggested doses to use (one mg/lb of body weight daily).  We only have limited 
feedback (at this time) on the use of HMRlignan.  In human studies with HMRlignan, single 
doses of 1,200 mg did not have any side effects (www.hmrlignan.com).  And in a chronic 
(13 week) study in rodents, 2,600 mg/kg of HMRlignan did not cause any toxic effects 
(www.cat.inist.fr).

Literature
SDG flax hull lignan.  See the article from the Lunus Pauling institute at Oregon State (www.
ipi.oregonstate.edu/infocenter/phytochemicals/lignans).

 

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