Dr Jack Oliver Treatment Option

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).